KR20230064355A - Pharmaceutical composition for preventing or treating pain comprising N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester compound as an active ingredient - Google Patents
Pharmaceutical composition for preventing or treating pain comprising N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester compound as an active ingredient Download PDFInfo
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- KR20230064355A KR20230064355A KR1020210149848A KR20210149848A KR20230064355A KR 20230064355 A KR20230064355 A KR 20230064355A KR 1020210149848 A KR1020210149848 A KR 1020210149848A KR 20210149848 A KR20210149848 A KR 20210149848A KR 20230064355 A KR20230064355 A KR 20230064355A
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- pain
- pharmaceutical composition
- trifluoromethyl
- tryptophan
- bis
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- -1 N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester compound Chemical class 0.000 title claims abstract description 23
- 239000004480 active ingredient Substances 0.000 title claims abstract description 9
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르 화합물을 유효성분으로 포함하는 통증의 예방 또는 치료용 약학적 조성물에 관한 것으로, 구체적으로 본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 통증의 예방 또는 치료용 약학적 조성물; 및 인간을 제외한 통증이 유발된 개체에 상기 본 발명의 약학적 조성물을 관절강 또는 척수강 내로 투여하는 단계를 포함하는 통증 치료방법에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating pain comprising an N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester compound as an active ingredient. Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester ((N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester) compound or a pharmaceutically acceptable salt thereof is effective A pharmaceutical composition for preventing or treating pain comprising as components; And it relates to a pain treatment method comprising the step of administering the pharmaceutical composition of the present invention into the joint cavity or the spinal cavity to a non-human subject whose pain is induced.
Description
본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르(N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester) 화합물을 유효성분으로 포함하는 통증의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to pain relief comprising an N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester compound as an active ingredient. It relates to a pharmaceutical composition for the prevention or treatment of.
통증은 부상이나 수술 후의 수백만의 사람들 및 관절염, 암 및 당뇨병과 같은 질환을 겪는 사람들에게 영향을 미친다. 통증은 발생부위, 원인, 성질 및 발생기전 등을 고려하여 구분할 수 있다.Pain affects millions of people after injuries or surgeries and those suffering from conditions such as arthritis, cancer and diabetes. Pain can be classified by considering the site of occurrence, cause, nature, and mechanism of occurrence.
통증은 그 지속기간에 따라서는 급성과 만성통증으로 나눌 수 있으며, 대표적인 만성통증 질환으로는 신경병증성 통증, 복합부위 통증 증후군, 대상포진 후 신경통, 척추 수술 후 통증 증후군 등이 있다. 만성통증은 단순히 급성통증의 연장선이 아니며, 통증의 정도는 원래의 손상 정도와 비례하지 않고 자극이 없이도 자발적으로 일어날 수 있다. 통증의 기간과 강도가 환자의 기능이나 생활에 유해한 효과를 일으키거나 또는 정상적인 조직 치유기간, 보통 3개월을 넘어서서 지속되는 경우는 만성통증으로 정의하며 증상이 아닌 하나의 질병으로 간주한다.Pain can be divided into acute and chronic pain depending on its duration, and typical chronic pain diseases include neuropathic pain, complex regional pain syndrome, postherpetic neuralgia, and post-spine surgery pain syndrome. Chronic pain is not simply an extension of acute pain, and the degree of pain is not proportional to the original level of damage and can occur spontaneously without stimulation. If the duration and intensity of pain cause adverse effects on the patient's function or life, or if it persists beyond the normal tissue healing period, usually 3 months, it is defined as chronic pain and is regarded as a disease rather than a symptom.
만성통증은 무자비하고 자기-제어적이지 않으며 초기 부상 후 수년 및 수십 년 까지도 지속될 수 있으며, 만성통증은 성질에 있어서 주로 신경병성이며 말초 또는 중추신경계 손상을 포함할 수 있다.Chronic pain is relentless and non-self-regulating and can persist for years and even decades after the initial injury, chronic pain is predominantly neuropathic in nature and may involve peripheral or central nervous system damage.
다양한 통증의 종류 중, 외견상으로는 상처나 동통의 원인이 없는데도 발생하는 통증이 바로 신경성 동통, 신경병증성 통증(neuropathic pain)이다. 신경병증성 통증은 암, 자가면역 질환 또는 대상포진 감염 등에 의한 신경 압박(nerve compression), 신경 외상(nerve trauma)과 같은 신경세포의 손상이나 신경계의 이상으로 생기는 통증을 총칭하며, 이는 정상적인 상태에서는 통증을 유발하지 않는 자극에도 통증반응을 보이는 이질통(allodynia)과 통증자극에 대해 더욱 민감한 반응을 보이는 통각과민(hyperalgesia), 또한, 자극이 없는 상태에서도 화끈거리거나 타는듯한 감각(spontaneous burning sensation)을 느끼는 등의 임상적 특성을 보이는 만성통증이다. 이와 같은 신경병증성 통증은 유해한 자극으로부터 신체를 보호하는 이로움을 주는 급성 통증과는 달리 통증을 전달하는 신경계의 변형으로 인해 질병 이상의 통증을 가져오게 된다.Among various types of pain, pain that occurs even though there is no apparent injury or cause of pain is neuropathic pain or neuropathic pain. Neuropathic pain is a generic term for pain caused by damage to nerve cells or abnormalities in the nervous system, such as nerve compression and nerve trauma caused by cancer, autoimmune disease, or herpes zoster infection. Allodynia, a painful response to non-painful stimuli, hyperalgesia, a more sensitive response to pain stimuli, and spontaneous burning sensation even in the absence of a stimulus It is chronic pain with clinical characteristics such as feeling. Such neuropathic pain, unlike acute pain, which benefits the body by protecting it from harmful stimuli, causes pain beyond disease due to deformation of the nervous system that transmits pain.
통증 치료에 있어서, 현재 사용되고 있는 통증 완화제, 즉 진통제는 아스피린 또는 타이레놀 등의 소염진통제가 주류를 이루고 있으며, 심한 통증에는 모르핀계 약물들을 사용되고 있고 이 외 케토프로펜 및 캡사이신 등이 크림이나 패치형태로 판매되고 있다. 다만 현재 사용되고 있는 이러한 통증 완화제들은 약리효과가 크지 못하고 부작용도 발생하고 있다. 아스피린 및 타이레놀은 그 복용 용량이 과도해지면 위 및 간에 독성을 야기하여 장애를 발생시킬 수 있고 알레르기를 유발한다. 또한 모르핀과 같은 오피오이드류(opioids) 진통제는 환자들에게서 강한 중독을 유발할 수 있고, 비스테로이드계 소염제(Non-Steroidal Anti Inflammatory Drugs: NSAIDs)는 오심, 구토, 변비 및 혈액 응고 등의 여러 가지 바람직하지 못한 부작용을 유발할 수 있어 부작용이 적거나 없고 통증 완화 및 치료효과가 우수한 새로운 통증 치료제의 개발이 필요하다.In the treatment of pain, currently used pain relievers, that is, analgesics, are mainly anti-inflammatory drugs such as aspirin or Tylenol, and morphine-based drugs are used for severe pain. It is on sale. However, these pain relievers currently used do not have a great pharmacological effect and cause side effects. Aspirin and Tylenol can cause toxicity to the stomach and liver if taken in excessive doses, resulting in disorders and allergies. In addition, opioids such as morphine can cause strong addiction in patients, and Non-Steroidal Anti Inflammatory Drugs (NSAIDs) have various undesirable effects such as nausea, vomiting, constipation and blood clotting. Therefore, it is necessary to develop new pain medications that have little or no side effects and have excellent pain relief and therapeutic effects.
한편, L-732,138[N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르(N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)] 화합물은 NK1(Neurokinin 1) 수용체의 길항제(antagonist)로서, 암 세포의 세포증식을 억제하고 세포사멸을 유도하는 항암 활성이 있음이 보고된 바 있고, 또한 심장 섬유증에 대한 예방 또는 치료효과가 있음을 보고된 바 있으나, 아직까지 L-732,138 약물이 통증의 개선 또는 치료 효과가 있다는 내용은 보고된 바 없다.On the other hand, the L-732,138 [N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester (N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester)] compound is NK1 ( As a neurokinin 1) receptor antagonist, it has been reported to have anti-cancer activity by inhibiting cell proliferation and inducing apoptosis of cancer cells, and it has also been reported to have preventive or therapeutic effects on cardiac fibrosis. However, there has been no report that the drug L-732,138 has pain amelioration or therapeutic effect.
이에 본 발명자들은 NK1(Neurokinin 1) 수용체의 길항제(antagonist) 중에서 L-732,138 화합물, 즉 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르 화합물이 통증을 완화 및 개선시킬 수 있을 뿐만 아니라 염증제어도 가능하여 새로운 통증 치료제로서의 사용 가능성을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors found that the L-732,138 compound, that is, the N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester compound, among NK1 (Neurokinin 1) receptor antagonists, can alleviate and improve pain. In addition to being able to control inflammation, the present invention was completed by confirming the possibility of use as a new pain treatment agent.
그러므로 본 발명의 목적은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 통증의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Therefore, an object of the present invention is N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester ((N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester)) compound or its It is to provide a pharmaceutical composition for preventing or treating pain, comprising a pharmaceutically acceptable salt as an active ingredient.
본 발명의 다른 목적은 인간을 제외한 통증이 유발된 개체에 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물을 관절강 또는 척수강 내로 투여하는 단계를 포함하는 통증 치료방법을 제공하는 것이다.Another object of the present invention is to treat pain-induced subjects other than humans with N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester ((N-Acetyl-L-tryptophan 3,5-bis( It is to provide a pain treatment method comprising the step of administering a trifluoromethyl) benzyl ester)) compound into a joint cavity or spinal cord.
그러므로 본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 통증의 예방 또는 치료용 약학적 조성물을 제공한다.Therefore, the present invention is N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester ((N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester)) compound or its pharmaceutical It provides a pharmaceutical composition for preventing or treating pain comprising an acceptable salt as an active ingredient.
본 발명의 일실시예에 있어서, 상기 조성물은 관절강 또는 척수강 내로 투여되는 것일 수 있다.In one embodiment of the present invention, the composition may be administered into the joint cavity or spinal cavity.
본 발명의 일실시예에 있어서, 상기 통증은 만성 통증(chronic pain)일 수 있다.In one embodiment of the present invention, the pain may be chronic pain.
본 발명의 일실시예에 있어서, 상기 만성 통증은 신경병증성 통증, 복합부위 통증 증후군, 대상포진 후 신경통 및 척추 수술 후 통증 증후군으로 이루어진 군 중에서 선택되는 것일 수 있다.In one embodiment of the present invention, the chronic pain may be selected from the group consisting of neuropathic pain, complex regional pain syndrome, post-herpetic neuralgia, and post-spinal surgery pain syndrome.
본 발명의 일실시예에 있어서, 상기 신경병증성 통증은 말초 신경 손상, 중추 신경 손상 및 염증성 신경 손상으로 이루어진 군으로부터 선택되는 1종 이상의 신경 손상에 의해서 유도되는 것일 수 있다.In one embodiment of the present invention, the neuropathic pain may be induced by at least one nerve injury selected from the group consisting of peripheral nerve injury, central nerve injury, and inflammatory nerve injury.
본 발명의 일실시예에 있어서, 상기 신경병증성 통증은 말초신경계 이상 또는 손상, 척수신경 손상을 포함한 다발성경화증, 척수부상, 통각과민, 감각과민, 신경병증, 당뇨성 신경장애, 신경염, 신경통, 작열통, 이질통, 포진후신경통, 요추 신경근압박, 암과 관련된 통증, 알코올 중독, 비정형 안면통증, 포진성 신경통, 중풍후통증, HIV 연관 신경병증, 골관절염 통증, 관절통증 및 환상사지통증으로 이루어진 군에서 선택되는 것일 수 있다. In one embodiment of the present invention, the neuropathic pain is peripheral nervous system abnormality or damage, multiple sclerosis including spinal nerve injury, spinal cord injury, hyperalgesia, hyperesthesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, In the group consisting of causal pain, allodynia, postherpetic neuralgia, lumbar nerve root compression, cancer-related pain, alcoholism, atypical facial pain, herpetic neuralgia, postparalytic pain, HIV-associated neuropathy, osteoarthritis pain, joint pain, and phantom limb pain may be selected.
본 발명의 일실시예에 있어서, 상기 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르 화합물은 SP(Substance P)/NK1(neurokinin 1)의 신호경로를 차단하는 활성을 통해 통증을 완화 또는 감소시키는 것일 수 있다.In one embodiment of the present invention, the N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester compound has the activity of blocking the SP (Substance P) / NK1 (neurokinin 1) signaling pathway It may be to alleviate or reduce pain.
본 발명의 일실시예에 있어서, 상기 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르 화합물은 항염증성 사이토카인의 발현을 증가시키는 것일 수 있다.In one embodiment of the present invention, the N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester compound may increase the expression of anti-inflammatory cytokines.
본 발명의 일실시예에 있어서, 상기 항염증성 사이토카인은 IL-6일 수 있다.In one embodiment of the present invention, the anti-inflammatory cytokine may be IL-6.
또한 본 발명은, 인간을 제외한 통증이 유발된 개체에 제1항의 조성물을 관절강 또는 척수강 내로 투여하는 단계를 포함하는 통증 치료방법을 제공한다.In addition, the present invention provides a pain treatment method comprising the step of administering the composition of claim 1 into the joint cavity or the spinal cavity to a non-human subject having pain.
본 발명에 따른 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르 화합물은 통증전달의 주요 경로가 되는 SP/NK1 신호경로를 차단할 수 있고 동시에 염증반응을 억제할 수 있으며, 통증 신호전달 물질의 발현을 억제할 수 있어 효과적인 통증 치료를 위한 새로운 치료제로 사용할 수 있다.The N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester compound according to the present invention can block the SP/NK1 signaling pathway, which is the main pathway of pain transmission, and at the same time suppress the inflammatory response. , it can suppress the expression of pain signaling substances, so it can be used as a new therapeutic agent for effective pain treatment.
도 1은 본 발명의 일실시예에서 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)에 L-732,138을 관절강 내로 주입 후(10 μM / 30 μl 주입) 통증 개선 정도를 분석한 결과로서, A는 약물 주입 후, 시간에 따른 PWT 측정 결과를, B는 MPE(maximal possible effect) 측정 결과를, C는 MPE를 토대로 한 AUC(Area under the curve) 분석 결과를 나타낸 것이다.
도 2는 본 발명의 일실시예에서 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)에 L-732,138을 척수강 내로 주입 후(10 μM / 10 μl 주입) 통증 개선 정도를 분석한 결과로서, A는 약물 주입 후, 시간에 따른 PWT 측정 결과를, B는 MPE(maximal possible effect) 측정 결과를, C는 MPE를 토대로 한 AUC(Area under the curve) 분석 결과를 나타낸 것이다.
도 3은 본 발명의 일실시예에서 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)에 L-732,138을 관절강 내로 농도별로 주입 후(10 μM, 1 μM, 100 nM / 30 μl 주입) 통증 개선 정도를 분석한 결과로서, A는 약물 주입 후, 시간에 따른 PWT 측정 결과를, B는 MPE(maximal possible effect) 측정 결과를, C는 MPE를 토대로 한 AUC(Area under the curve) 분석 결과를 나타낸 것이다.
도 4는 본 발명의 일실시예에서 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)에 L-732,138을 척수강 내로 농도별로 주입 후(10 μM, 1 μM, 100 nM / 10 μl 주입) 통증 개선 정도를 분석한 결과로서, A는 약물 주입 후, 시간에 따른 PWT 측정 결과를, B는 MPE(maximal possible effect) 측정 결과를, C는 MPE를 토대로 한 AUC(Area under the curve) 분석 결과를 나타낸 것이다.
도 5는 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)의 관절강 또는 척수강 내로 L-732,138 약물을 10 μM 주입하고 9시간 후, 관절 활막(synovial membrane)에서의 CGRP(Calcitonin gene-related peptide) 및 SP(Substance P)의 발현정도를 면역형광법으로 확인한 결과를 나타낸 것이다.
도 6은 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)의 관절강 또는 척수강 내로 L-732,138 약물을 10 μM 주입하고 9시간 후, 척수에서의 Calcitonin CGRP(Calcitonin gene-related peptide) 및 SP(Substance P)의 발현정도를 면역조직화학법으로 확인한 결과를 나타낸 것이다.
도 7은 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)의 관절강 또는 척수강 내로 L-732,138 약물을 10 μM 주입하고 9시간 후, 척수에서의 extracellular NK1 수용체 및 IL-6(interleukin-6) 의 발현정도를 단백질 정량 분석을 통해 확인한 결과를 나타낸 것이다.
도 8은 랫드 (흰쥐, 또는 백서) 동물을 대상으로 von Frey filament를 이용하여 자극에 대한 회피반응역치를을 PWT(Paw withdrawal threshold) 평가로 확인하는 과정을 나타낸 것이다.
도 9는 랫드 (흰쥐, 또는 백서) 동물을 대상으로 약물의 관절강 내로의 주입방식을 나타낸 것이다.
도 10은 랫드 (흰쥐, 또는 백서) 동물을 대상으로 약물의 척수강 내로의 주입방식을 나타낸 것이다.1 is a result of analyzing the degree of pain improvement after injecting L-732,138 into the joint cavity (10 μM / 30 μl injection) in a rat (white rat or white paper) induced with chronic joint pain in one embodiment of the present invention, A A shows the PWT measurement result over time after drug injection, B shows the maximal possible effect (MPE) measurement result, and C shows the AUC (Area under the curve) analysis result based on the MPE.
2 is a result of analyzing the degree of pain improvement after intrathecal injection of L-732,138 (10 μM / 10 μl injection) into a rat (white rat or white paper) induced with chronic joint pain in one embodiment of the present invention, A A shows the PWT measurement result over time after drug injection, B shows the maximal possible effect (MPE) measurement result, and C shows the AUC (Area under the curve) analysis result based on the MPE.
Figure 3 shows the improvement of pain after injecting L-732,138 into the joint cavity by concentration (10 μM, 1 μM, 100 nM / 30 μl injection) in rats (white rats or white papers) induced with chronic joint pain in one embodiment of the present invention. As a result of analyzing the degree, A is the PWT measurement result over time after drug injection, B is the maximal possible effect (MPE) measurement result, and C is the AUC (Area under the curve) analysis result based on MPE. will be.
Figure 4 is an embodiment of the present invention after injection of L-732,138 into the spinal cavity by concentration (10 μM, 1 μM, 100 nM / 10 μl injection) in rats (white rats or white papers) induced with chronic joint pain, pain improvement As a result of analyzing the degree, A is the PWT measurement result over time after drug injection, B is the maximal possible effect (MPE) measurement result, and C is the AUC (Area under the curve) analysis result based on MPE. will be.
Figure 5 shows CGRP (Calcitonin gene-related peptide) in the joint
Figure 6 is 9 hours after injecting 10 μM of L-732,138 drug into the joint cavity or spinal cord of rats (rats or white papers) induced with chronic joint pain, Calcitonin CGRP (Calcitonin gene-related peptide) and SP (Substance) in the spinal cord P) shows the result of confirming the expression level of immunohistochemistry.
7 shows the effects of extracellular NK1 receptors and interleukin-6 (IL-6) in the
8 shows a process of confirming the avoidance response threshold to a stimulus using a von Frey filament in a rat (white rat or white paper) animal by Paw withdrawal threshold (PWT) evaluation.
9 shows a method of injecting a drug into the joint cavity of a rat (white rat or white paper) animal.
10 shows a method of intrathecal injection of a drug into a rat (white rat or white paper) animal.
본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르, 즉 L-732,138 화합물의 새로운 의약용도로서, 통증 치료제로서의 사용 가능성을 제공함에 특징이 있다.The present invention is characterized in that N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester, that is, L-732,138 compound, is used as a new medicinal use, as a therapeutic agent for pain.
구체적으로 본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 통증의 예방 또는 치료용 약학적 조성물을 제공함에 특징이 있다.Specifically, the present invention relates to N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester ((N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester)) compound or its pharmaceutical It is characterized in that it provides a pharmaceutical composition for preventing or treating pain, including an acceptable salt as an active ingredient.
본 발명에서 상기 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물은 NK1(Neurokinin 1) 수용체의 길항제(antagonist)로서 항암 활성을 가지고 있으며 심장 섬유증에 대한 치료 효과가 있다는 연구가 보고된 바 있으나, 통증 치료 효능이 있다는 결과는 보고된 바가 없었다.In the present invention, the N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester ((N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester)) compound is NK1 (Nurokinin 1) As a receptor antagonist, it has anticancer activity and studies have been reported that it has a therapeutic effect on cardiac fibrosis, but no results have been reported that it has a therapeutic effect on pain.
한편, 본 발명자들은 부작용이 적으면서 효과적으로 통증을 제어할 수 있는 새로운 통증 치료제로서 L-732,138 화합물이 사용 가능함을 실험을 통해 확인하였다.On the other hand, the present inventors confirmed through experiments that the L-732,138 compound can be used as a novel pain treatment that can effectively control pain with fewer side effects.
이와 관련하여 본 발명의 일실시예에서는, 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서), 즉 관절염 유발 후 실질적 만성 통증 유지단계에 있는 통증 후기의 랫드 (흰쥐, 또는 백서)에 L-732,138 화합물을 투여한 후, 통증의 완화 정도를 분석하였는데, 그 결과, L-732,138 화합물을 투여한 군이 상기 약물 대신 생리식염수 (saline)을 투여한 대조군에비해 통증이 효과적으로 완화되는 것을 확인할 수 있었다.In this regard, in one embodiment of the present invention, L-732,138 was applied to rats (white rats or white papers) in which chronic joint pain was induced, that is, rats in the late phase of pain (white rats or white papers) in the substantial chronic pain maintenance phase after inducing arthritis. After administering the compound, the degree of pain relief was analyzed. As a result, it was confirmed that the group administered with the L-732,138 compound effectively relieved pain compared to the control group administered with saline instead of the drug.
또한 본 발명의 다른 일실시예에서는, 본 발명의 L-732,138 화합물 투여 경로에 따른 통증 개선 정도를 분석하였는데, 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)에 대하여 관절강 내로 약물을 투여한 군과 척수강 내로 약물을 투여한 군에 대한 통증 개선 정도 분석 결과, 관절강 투여에 비해 척수강 내로의 투여 시, 더 적은 농도의 약물 투여로도 통증을 효과적으로 개선할 수 있는 것으로 나타났다.In addition, in another embodiment of the present invention, the degree of pain improvement according to the administration route of the L-732,138 compound of the present invention was analyzed. As a result of analyzing the degree of pain improvement in the group administered intrathecally and intrathecally, it was found that pain could be effectively improved with a lower concentration of drug when administered intrathecally compared to intraarticular administration.
본 발명의 또 다른 일실시예에서는, L-732,138 화합물이 어떠한 활성을 통해 통증을 개선 또는 치료할 수 있는지 확인하기 위해, 만성관절통증이 유발된 랫드 (흰쥐, 또는 백서)에 L-732,138 화합물을 투여 후, 통증 전달에 관여하는 신경 펩타이드인 CGRP(calcitonin gene-related peptide) 및 SP(susbstance P)의 발현에 변화를 미치는지를 분석하였다.In another embodiment of the present invention, in order to determine whether L-732,138 compound can improve or treat pain through any activity, L-732,138 compound was administered to rats (rats or white papers) induced with chronic joint pain Afterwards, changes in the expression of calcitonin gene-related peptide (CGRP) and sustainstance P (SP), which are neuropeptides involved in pain transmission, were analyzed.
그 결과, L-732,138 화합물 투여군이 대조군에 비해 통증 전달에 관여하는 신경 펩타이드들의 발현이 감소되어 있는 것으로 나타났다.As a result, it was found that the expression of neuropeptides involved in pain transmission was decreased in the L-732,138 compound administration group compared to the control group.
뿐만 아니라, L-732,138 화합물 투여군은 대조군에 비해 항염증성 사이토카인인 IL-6의 발현수준도 감소되어 있는 것으로 나타났다.In addition, the expression level of IL-6, an anti-inflammatory cytokine, was also found to be reduced in the L-732,138 compound-administered group compared to the control group.
이러한 결과를 통해 본 발명자들은 본 발명의 L-732,138 화합물은 통증을 유발하는 SP-NK1 신호를 차단하는 활성을 통해 통증 신호 전달 감소 효과와 항염증 활성을 동시에 가짐으로써 효과적으로 통증을 예방 또는 치료할 수 있음을 알 수 있었다.Through these results, the present inventors found that the L-732,138 compound of the present invention has pain signal transmission reducing effect and anti-inflammatory activity at the same time through the activity of blocking the pain-inducing SP-NK1 signal, thereby effectively preventing or treating pain And it was found.
그러므로 본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 통증의 예방 또는 치료용 약학적 조성물을 제공할 수 있다.Therefore, the present invention is N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester ((N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester)) compound or its pharmaceutical It is possible to provide a pharmaceutical composition for preventing or treating pain comprising an acceptable salt as an active ingredient.
본 발명에서 상기 통증은 만성 통증(chronic pain)일 수 있다. ‘만성 통증질환’은 몸의 한 곳 또는 여러 곳에 영향을 주고 3개월 이상 지속되는 다소 심한 고통을 의미하며, 시간이 지남에 따라 그 강도가 달라질 수 있는 통증 증후군을 포함한다.In the present invention, the pain may be chronic pain. ‘Chronic pain disorder’ means moderately severe pain that affects one or several parts of the body and lasts for more than 3 months, and includes pain syndromes that may vary in intensity over time.
상기 만성 통증은 이에 제한되지는 않으나, 신경병증성 통증, 복합부위 통증 증후군, 대상포진 후 신경통 또는 척추 수술 후 통증 증후군을 포함한다.The chronic pain includes, but is not limited to, neuropathic pain, complex regional pain syndrome, post-herpetic neuralgia or post-spinal surgery pain syndrome.
상기 ‘신경병증성 통증’은 말초 신경 손상, 중추 신경 손상 또는 신경성 염증 (neurogenic inflammation)에 의해서 유도될 수 있으며, 구체적으로 상기 신경병증성 통증은 이에 제한되지는 않으나, 말초신경계 이상 또는 손상, 척수신경 손상을 포함한 다발성경화증, 척수부상, 통각과민, 감각과민, 신경병증, 당뇨성 신경장애, 신경염, 신경통, 작열통, 이질통, 포진후신경통, 요추 신경근압박, 암과 관련된 통증, 알코올 중독, 비정형 안면통증, 포진성 신경통, 중풍후통증, HIV 연관 신경병증, 골관절염 통증, 관절통증 및 환상사지통증을 포함할 수 있다.The 'neuropathic pain' may be induced by peripheral nerve damage, central nerve damage, or neurogenic inflammation, and specifically, the neuropathic pain is not limited thereto, but is not limited thereto, peripheral nervous system abnormality or damage, spinal cord Multiple sclerosis including nerve damage, spinal cord injury, hyperalgesia, hyperesthesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, causalgia, allodynia, postherpetic neuralgia, lumbar nerve root compression, cancer-related pain, alcoholism, atypical facial pain, herpetic neuralgia, postparalytic pain, HIV-associated neuropathy, osteoarthritis pain, joint pain and phantom limb pain.
본 발명의 L-732,138 화합물이 치료할 수 있는 대상질환은 상기 기재된 통증 질환을 모두 포함할 수 있으며, 본 발명의 일실시예에서는 만성통증에 속하며 신경병증성 통증에 해당하는 만성 관절통증이 유발된 랫드 (흰쥐, 또는 백서) 동물모델을 대상으로 L-732,138 화합물의 치료 효능을 확인하였다.Target diseases that can be treated by the L-732,138 compound of the present invention may include all of the above-described pain diseases, and in one embodiment of the present invention, rats induced with chronic joint pain belonging to chronic pain and corresponding to neuropathic pain (Rat or white paper) The therapeutic efficacy of the L-732,138 compound was confirmed in an animal model.
특히 본 발명의 일실시예에서는, L-732,138 화합물이 관절염 발생 이후 신경의 가소적 변화를 야기하여 만성 통증을 유발하는 SP-NK1의 신호를 차단하는 활성이 있음을 확인하였다.In particular, in one embodiment of the present invention, it was confirmed that the L-732,138 compound has an activity to block the signal of SP-NK1, which induces chronic pain by causing plastic changes in nerves after the onset of arthritis.
SP(Substance P) 물질은 감각신경으로부터 말초와 척수로 분비되어 신경성 염증을 일으켜 만성 염증반응을 야기하며 통증 전달에 관여하는 NK1 수용체(neurokinin1 receptor)를 활성화시켜 통증전달 신경섬유의 활동을 증가시킴으로써 중추 감작화 (central sensitization)로 인해 통각과민(hyperalgesia)을 유발시킨다.Substance P (SP) substances are secreted from sensory nerves to the periphery and spinal cord to cause neurogenic inflammation, resulting in a chronic inflammatory response, and by activating NK1 receptors (neurokinin1 receptors) involved in pain transmission to increase the activity of pain transmission nerve fibers, resulting in central Central sensitization causes hyperalgesia.
따라서 SP(Substance P)는 초기 염증반응과 통증발생에 관여하며 염증과 통증의 악순환을 야기하는 신경성염증에 관여할 뿐만 아니라 만성통증의 주요한 기전인 중추신경계의 흥분성 증가에 관여하는 중요한 인자이다.Therefore, SP (Substance P) is involved in the initial inflammatory response and pain generation, and is involved in neurogenic inflammation, which causes a vicious cycle of inflammation and pain, as well as an important factor involved in increased excitability of the central nervous system, which is a major mechanism of chronic pain.
손상된 말초신경은 글루타메이트, CGRP(calcitonin gene-related peptide) 및 SP(Substance P) 물질 등을 분비하는데, 이 물질들은 척수에서 유해한 자극에 대한 흥분성을 증가시키며, 주위의 억제성 사이신경세포의 기능을 방해하는 신경 전달물질이나 신경 페타이드를 분비하고, 이렇게 분비된 물질들은 통증의 전달을 악화시킨다.Damaged peripheral nerves secrete glutamate, CGRP (calcitonin gene-related peptide), and SP (Substance P) substances, which increase excitability in response to noxious stimuli in the spinal cord and inhibit the function of surrounding inhibitory interneurons. They release interfering neurotransmitters or neuropetides, which exacerbate the transmission of pain.
또한, 관절염이 유발된 관절 내에서 지속적인 염증반응과 관절 활액막 내 SP의 발현이 증가되어 있다고 보고된 바 있다. 따라서 난치성 만성 관절 통증의 발생 기전은 말초 통각신경과 신경성 염증(neurogenic inflammation)에 따른 척수의 중추감작화(central sensitization)가 관여하고 있다고 볼 수 있다.In addition, it has been reported that a continuous inflammatory response and an increased expression of SP in the synovial membrane of a joint in an arthritic joint have been reported. Therefore, it can be seen that the mechanism of occurrence of intractable chronic joint pain involves central sensitization of the spinal cord due to peripheral nociceptive nerves and neurogenic inflammation.
또한, 이전에는 염증반응이 통증, 특히 신경변성 통증과는 상관성이 없다고 여겨졌으나, 최근에는 말초신경에서의 염증 반응이 신경병성 통증의 발생에 중요한 역할을 한다고 알려지고 있어, 통증과 함께 염증이 조절되어야 효과적으로 통증을 제어할 수 있다.In the past, it was thought that the inflammatory response had nothing to do with pain, especially neurodegenerative pain, but recently it has been known that the inflammatory response in peripheral nerves plays an important role in the development of neuropathic pain, and inflammation is regulated along with pain. You must be able to effectively control your pain.
그러므로 만성 통증을 효과적으로 치료하기 위해서는 SP/NK1 신호를 차단하여 염증반응을 억제하고, 신생 통증신경 신호전달 및 통증 신호전달을 차단할 수 있어야 한다.Therefore, in order to effectively treat chronic pain, it is necessary to suppress the inflammatory response by blocking the SP/NK1 signal and to block the new pain nerve signal transmission and pain signal transmission.
이러한 점에서 본원발명의 L-732,138 화합물은 SP/NK1 신호차단 활성을 가지며 동시에 염증반응을 억제할 수 있고, 통증 신호전달 물질의 발현을 억제할 수 있어 근본적이고 효과적인 통증 치료가 가능하다는 것을 확인하였다.In this respect, it was confirmed that the L-732,138 compound of the present invention has SP/NK1 signaling blocking activity, can simultaneously inhibit inflammatory reactions, and can inhibit the expression of pain signaling substances, enabling fundamental and effective pain treatment. .
본 발명에서 제공하는 상기 조성물은 약학적으로 허용되는 담체를 포함한다. 본 발명의 약학적 조성물에 포함되며 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘, 미네랄오일, 식염수, PBS(phosphate buffered saline) 또는 배지 등을 포함하나, 이에 한정되는 것은 아니다.The composition provided by the present invention includes a pharmaceutically acceptable carrier. Acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, saline, phosphate buffered saline (PBS) or medium, etc., but is not limited thereto.
상기 용어 '약학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다.The term 'pharmaceutically acceptable' refers to a composition that is physiologically acceptable and does not usually cause allergic reactions or similar reactions when administered to humans.
본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다 (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations may be referenced as described in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995.
비경구 투여용 제제의 경우에는 주사제의 형태로 당업계에 공지된 방법으로 제형화 할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour)에 기재되어 있다.In the case of a formulation for parenteral administration, it may be formulated in the form of an injection by a method known in the art. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, which is a generally known formula for all pharmaceutical chemistry.
본 발명의 약학적 조성물은 경구 또는 비경구 투여할 수 있으며, 예를 들어, 척수 내, 정맥 내, 근육 내, 동맥 내, 골수 내, 경막 내, 심장 내, 경피, 피하, 복강 내, 비강 내, 장관, 국소, 설하 또는 직장 내 투여일 수 있으며, 바람직하게는 관절강 또는 척수강 내로 투여될 수 있고, 통증 치료를 위한 추가적인 성분을 포함하여 함께, 동시에, 순차적으로 사용할 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally, for example, intraspinal, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal , It can be enteral, topical, sublingual or rectal administration, preferably intraarticular or intrathecal, and can be used together, simultaneously or sequentially, including additional components for pain treatment.
상기 '척수강 내 투여' 란 본 발명의 약학적 조성물을 척수강 내에 투여하여 만성통증 질환, 예컨대 신경병증성 통증의 예방 또는 치료용 약학적 조성물에 함유된 활성성분이 척수 내로 전달되도록 하는 것을 말한다.The 'intrathecal administration' refers to administering the pharmaceutical composition of the present invention intrathecally so that the active ingredient contained in the pharmaceutical composition for preventing or treating chronic pain diseases, such as neuropathic pain, is delivered into the spinal cord.
또한 본 발명의 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에서 "약제학적으로 유효한 양"은 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도; 환자의 연령, 체중, 건강, 성별; 환자의 약물에 대한 민감도; 투여 시간, 투여 경로 및 배출 비율; 치료 기간; 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 알려진 요소에 따라 결정될 수 있다. 바람직하게는, 본 발명의 약학적 조성물은 질환의 정도에 따라 유효량을 달리할 수 있으나, 바람직하게는 150~5000㎍/60kg/day, 더욱 바람직하게는 500~1500㎍ /60kg/day의 유효량으로 하루에 수회 반복 투여될 수 있다. 상기 조성물의 투여량은 어떠한 방법으로도 본 발명의 범위를 한정하는 것이 아니다.In addition, the composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease, and the effective dose level depends on the severity of the disease; the age, weight, health, and sex of the patient; the patient's sensitivity to the drug; time of administration, route of administration and rate of excretion; duration of treatment; It may be determined according to factors including drugs used in combination or simultaneous use with the composition of the present invention used and other factors known in the medical field. Preferably, the pharmaceutical composition of the present invention may vary in effective amount depending on the severity of the disease, but preferably in an effective amount of 150 to 5000 μg/60 kg/day, more preferably 500 to 1500 μg/60 kg/day. It may be administered repeatedly several times a day. The dosage of the composition is not intended to limit the scope of the present invention in any way.
본 발명의 약학적 조성물은 포유동물, 예를 들어 인간 및 인간을 제외한 포유동물에 투여할 수 있으나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may be administered to mammals, for example, humans and non-human mammals, but is not limited thereto.
또한 본 발명은 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르((N-Acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester)) 화합물을 개체에 투여하여 통증을 치료하는 방법을 제공할 수 있다.In addition, the present invention administers N-Acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester) compound to a subject This can provide a way to treat pain.
이때 상기 투여는 관절강 또는 척수강 내로의 투여일 수 있다.In this case, the administration may be administration into a joint cavity or a spinal cavity.
상기 개체는 개과 동물, 고양이과 동물, 멧돼지과 동물, 소과 동물, 사슴과 동물, 기린과 동물, 페커리과 동물, 낙타과 동물, 하마과 동물, 말과 동물, 맥과 동물, 코뿔소과 동물, 족제비과, 토끼과, 설치류 및 영장류를 포함하나, 이에 한정되지 않는다.The subject canine, feline, wild boar, bovine, deer, giraffe, peccary, camel, hippo, horse, tapir, rhinoceros, weasel, lagomorph, rodent and Including, but not limited to, primates.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. These examples are intended to explain the present invention in more detail, and the scope of the present invention is not limited to these examples.
<준비예 및 실험방법><Preparation examples and experimental methods>
① 실험동물의 준비① Preparation of experimental animals
본 발명의 실시예에서 사용한 동물은 Sprague-Dawley (SD) 랫드(rat)를 사용하였고, 동물은 12시간의 광 / 12시간의 암 주기 하에 음식과 물을 자유롭게 공급하며 사육하였다. 동물보호 및 통증시험을 비롯한 모든 행동 시험은 고려대학교 산하 동물 실험 협의회(Institutional Aimal Care and Use Committee)의 윤리적 지침 하에 수행하였다.Animals used in the Examples of the present invention were Sprague-Dawley (SD) rats, and the animals were raised under a 12-hour light / 12-hour dark cycle with free supply of food and water. All behavioral tests, including animal protection and pain tests, were performed under the ethical guidelines of the Institutional Aimal Care and Use Committee affiliated with Korea University.
② MIA(Monosodium idoacetate) 투여를 통한 만성관절통증 동물모델의 제조② Manufacture of chronic joint pain animal model through MIA (Monosodium idoacetate) administration
MIA로 유발된 관절염 모델은 골관절염 모델 중 하나로서, 관절 내 연골세포에 glyceraldehyde-3 phosphate dehydrogenase의 활성을 저해하여 해당과정을 억제시켜 세포사멸을 유도하여 연골을 퇴행시키는 것으로 알려져 있다. 이에 본 발명자들은 180~200g의 Sprague-Dawley (SD rat) 사용하여, 혼합제재의 마취 가스(3% isoflurane + 97% Oxygen)를 마스크를 이용하여 흡입 마취시켰고, Pedal reflex로 마취 확인하였다. 이후 오른쪽 무릎 관절강 내에 30G 인슐린 시린지(Insulin syringe)를 이용하여 MIA(4㎎의 MIA이 50 ㎕에 용해된 살린용액, Sigma, St Louis, MO, USA)를 주입시켜 만성관절통증 동물모델을 제조하였다.The arthritis model induced by MIA is one of the osteoarthritis models, and it is known to degenerate cartilage by inhibiting the activity of glyceraldehyde-3 phosphate dehydrogenase in chondrocytes in the joint to inhibit glycolysis and inducing apoptosis. Accordingly, the present inventors used 180-200 g of Sprague-Dawley (SD rat), inhaled anesthesia with a mixed anesthetic gas (3% isoflurane + 97% Oxygen) using a mask, and confirmed anesthesia with Pedal reflex. Then, by injecting MIA (saline solution in which 4 mg of MIA was dissolved in 50 μl, Sigma, St Louis, MO, USA) using a 30G insulin syringe into the joint cavity of the right knee, an animal model for chronic joint pain was prepared. .
③ 자극에 대한 반응분석(von Frey filament test)③ Analysis of responses to stimuli (von Frey filament test)
관절염 유발 후와 L-732,138 주입에 따른 진통효과를 평가 방법으로서, 발의 기계적 민감성을 정량화하기 위해 업/다운 방법을 이용하여 본 프레이 필라멘트에 대한 발 회피 역치를 측정하였다(도 8 참조). 발바닥의 감각변화 측정을 위해 쥐를 스테인레스 스틸 메쉬(stainless steel mesh)위에 있는 투명 케이즈(10x10x28 cm)에 넣고 새로운 환경에 적응되기까지(약 20분) 아무런 처치도 하지 않고 기다렸다. 쥐가 새로운 환경에 완전히 적응한 후 각기 다른 힘을 가진 8개의 본 프레이 필라멘트(von Frey filament 0.4, 0.6, 1, 2, 4, 6, 8, 15 g; Stoelting, Wood Dale, IL, USA)를 이용하여 50 % 회피 역치(50 % paw withdrawal threshold)를 측정하였다. 본 프레이 필라멘트 적용에 대한 활발한 발 들어올리기(foot lift)는 회피 반응으로 간주하였다. 제 1 자극은 2 g 이었으며, 회피 반응이 있는 경우 그 다음 약한 필라멘트를 적용하였으며, 반응이 없는 경우에는 그 다음 강한 필라멘트를 적용하였다. 50 % 역치의 내삼법(Interpolation)을 딕슨(Dixon, 1980)의 방법에 따라 수행하였다.As a method for evaluating the analgesic effect following the induction of arthritis and injection of L-732,138, the paw avoidance threshold for the von Frey filament was measured using the up/down method to quantify the mechanical sensitivity of the paw (see FIG. 8). To measure sensory changes in the soles of the feet, the rats were placed in a transparent cage (10x10x28 cm) on a stainless steel mesh and waited without any treatment until they were adapted to the new environment (about 20 minutes). Eight von Frey filaments (0.4, 0.6, 1, 2, 4, 6, 8, 15 g; Stoelting, Wood Dale, IL, USA) with different strengths were injected after the rats fully adapted to the new environment. 50% paw withdrawal threshold was measured using Vigorous foot lift in response to von Frey filament application was considered an avoidance response. The first stimulus was 2 g, and if there was an avoidance response, the next weak filament was applied, and if there was no response, the next strong filament was applied. Interpolation with a 50% threshold was performed according to the method of Dixon (1980).
또한, 발바닥의 감각변화는 관절염 유발 전과 후, 약물 주입 전과 주입 후 시간경과에 따라 검사를 수행하였는데, 검사는 하지의 회피능력을 근간으로 하고 있으므로 운동기능의 검사를 병행하고 분석 시 반드시 고려해야한다. 정상적인 쥐에선 거의 회피반응을 볼 수 없으나 기계적 자극으로 인해 통증이 발생한 동물에서는 급격한 회피반응을 보이게 되는데 이를 기계적 이질통의 지표로 하였다.In addition, sensory changes in the soles of the feet were tested before and after the onset of arthritis and before and after drug injection according to the lapse of time. Since the test is based on the avoidance ability of the lower extremities, it must be considered in parallel with the test of motor function and analysis. Almost no avoidance response was seen in normal rats, but animals experiencing pain due to mechanical stimulation showed a sharp avoidance response, which was used as an indicator of mechanical allodynia.
약물 효능 평가를 위해, 측정한 기계적 이질통(mechanical allodynia) 수치를 이용하여 MPE(Maximal possible effect) 및 MPE의 AUC(Area under the curve)를 산출하였다.For drug efficacy evaluation, MPE (Maximal possible effect) and AUC (Area under the curve) of MPE were calculated using the measured mechanical allodynia values.
④ L-732,138 약물의 준비④ Preparation of L-732,138 drug
본 실험에서 L-732,138 약물은(Tocris, 0868, Avonmouth, Bristol, UK) 제조사의 프로토콜에 따라 10mg을 100% 에탄올 21.17 ml에 첨가하여 1mM stock 용액을 제조한 후, 살린 용액으로 원하는 농도로 희석하여 주입 시 사용하였다.In this experiment, 10 mg of L-732,138 drug (Tocris, 0868, Avonmouth, Bristol, UK) was added to 21.17 ml of 100% ethanol to prepare a 1 mM stock solution according to the manufacturer's protocol, and then diluted with saline solution to the desired concentration. Used for injection.
⑤ 관절염 유발 후, 관절강 내로의 L-732,138 약물 주입⑤ After inducing arthritis, L-732,138 drug injection into the joint cavity
PWT를 통해 통증 발생 확인 후(PWT < 1 g), 약물 주입을 수행하였는데, 관절강 내로의 약물 주입을 위해, 혼합제재의 마취 가스(3% isoflurane + 97% Oxygen)를 마스크를 이용하여 흡입마취(Pedal reflex로 마취 확인) 시킨 후, 오른쪽 무릎 관절강 내에 30G 인슐린 시린지를 이용하여 L-732,138 을 주입하였다(도 9 참조).After confirming the occurrence of pain through PWT (PWT < 1 g), drug injection was performed. To inject the drug into the joint cavity, inhalation anesthesia using a mixed anesthetic gas (3% isoflurane + 97% Oxygen) using a mask After anesthesia was confirmed by pedal reflex), L-732,138 was injected into the joint cavity of the right knee using a 30G insulin syringe (see FIG. 9).
⑥ 관절염 유발 후, 척수강 내로의 L-732,138 약물 주입⑥ After inducing arthritis, L-732,138 drug injection into the spinal canal
PWT를 통해 통증 발생 확인 후(PWT < 1 g), 약물 주입을 수행하였는데, 척수강 내로의 약물 주입을 위해, 혼합제재의 마취 가스(3% isoflurane + 97% Oxygen)를 마스크를 이용하여 흡입마취(Pedal reflex로 마취 확인)시켰다. 이때 시술 시 체온 유지를 위하여 Hot pad를 켜고 진행하였다. 마취 후, 시술부위의 털을 제거 한 다음, 70% 에탄올 및 Povidone-iodine cotton ball을 이용하여 국소 소독을 3회 수행하였다. Scissor를 이용하여 요추 4번과 5번 (L4, L5) 주변 근육을 제거한 후 론저를 이용하여 spine 사이의 근육을 제거하였고, 18G 주사바늘을 L4와 L5 spine 사이에 미세히 삽입 후, 주사바늘을 통해 PE10 튜브를 약 3cm 가량 삽입하였다. 삽입된 PE10 튜브 반대쪽 끝에 30G 인슐린 시린지를 이용하여 L-732,138 약물을 주입하였다. 이후 바늘을 제거한 다음, 근육 및 피부를 3-0 silk를 이용하여 봉합하였다.After confirming the occurrence of pain through PWT (PWT < 1 g), drug injection was performed. For drug injection into the spinal canal, inhalation anesthesia using a mixed anesthetic gas (3% isoflurane + 97% Oxygen) using a mask ( Anesthesia was confirmed by pedal reflex). At this time, the hot pad was turned on to maintain body temperature during the procedure. After anesthesia, hair was removed from the treatment area, and then local disinfection was performed three times using 70% ethanol and Povidone-iodine cotton balls. After removing the muscles around the 4th and 5th lumbar vertebrae (L4, L5) using a scissor, the muscles between the spines were removed using a Longer, and after finely inserting an 18G injection needle between the L4 and L5 spines, the injection needle A PE10 tube was inserted about 3 cm through the tube. L-732,138 was injected using a 30G insulin syringe at the opposite end of the inserted PE10 tube. After removing the needle, the muscle and skin were sutured using 3-0 silk.
⑦ 관절염 유발 후, 관절강 및 척수강 내로의 L-732,138 주입 9시간 후 조직 적출 및 조직학적 검사 시행⑦ After induction of arthritis, tissue extraction and histological examination were performed 9 hours after L-732,138 injection into the joint cavity and spinal cavity
면역형광법 : 아베르틴(Avertin) 및 부탄올(Butanol)의 혼합액을 1200 -1500 mg/kg로 쥐의 복강 내로 주입하고, 마취 후 0.9% 살린 용액으로 심장 관류하여 혈액 제거와 동시에 안락사 진행 후 관류 고정시켰다. 그런 뒤, 무릎관절 연골과 골조직을 적출하여, 10% 중성 버퍼의 포르말린(neutral buffered formalin)과 1% CPC(cetylpyridinium chloride)에서 1일간 고정 후, EDTA(ethylene-diamine tetra acetic acid)로 탈석회화하고 OCT로 포매한 후, 시상면으로 절편을 만들었다. OCT 포매한 조직절편을 1차 항체로 통증 신호 전달 신경펩타이드인 CGRP와 SP의 항체를 반응시키고, 2차 항체 반응 후 형광을 띄는 Alexa flour dye로 염색하여 형광현미경으로 관찰하였다.Immunofluorescence method: A mixed solution of Avertin and Butanol was injected into the abdominal cavity of the rat at 1200 -1500 mg/kg, and after anesthesia, the heart was perfused with 0.9% saline solution to remove blood and euthanized at the same time, followed by perfusion fixation. made it Then, the knee joint cartilage and bone tissue were extracted, fixed in 10% neutral buffered formalin and 1% CPC (cetylpyridinium chloride) for 1 day, and then decalcified with EDTA (ethylene-diamine tetra acetic acid). After embedding with OCT, sagittal sections were made. OCT-embedded tissue sections were reacted with the pain signal transmission neuropeptide CGRP and SP antibodies with the primary antibody, and after the reaction with the secondary antibody, they were stained with fluorescent Alexa flour dye and observed under a fluorescence microscope.
면역조직화학법 : 아베르틴(Avertin) 및 부탄올(Butanol)의 혼합액을 1200 -1500 mg/kg 로 쥐의 복강 내로 주입하고, 마취 후 0.9% 살린 용액으로 심장 관류하여 혈액 제거와 동시에 안락사 진행 후 관류고정시켰다. 무릎관절지배 수준의 척수(L3-5)를 적출하였고, 후고정한 다음, OCT에 포매한 조직을 냉동절편 후 CGRP와 SP의 면역조직화학법(DAB 염색)을 시행하였다.Immunohistochemistry: A mixed solution of Avertin and Butanol was injected into the abdominal cavity of the rat at 1200 -1500 mg/kg, and after anesthesia, the heart was perfused with 0.9% saline solution to remove blood and euthanized at the same time. perfusion was fixed. The spinal cord (L3-5) at the level of the knee joint was excised, post-fixed, and the tissues embedded in OCT were cryosectioned and subjected to CGRP and SP immunohistochemistry (DAB staining).
웨스턴 블롯 : 아베르틴(Avertin) 및 부탄올(Butanol)의 혼합액을 1200 -1500 mg/kg 로 쥐의 복강 내로 주입하고, 마취 후 0.9% 살린 용액으로 심장 관류하여 혈액 제거와 동시에 안락사 진행 후 관류고정시켰다. 무릎관절지배 수준의 척수(L3-5)를 적출하였다. 단백질 용출용액으로 조직을 파쇄한 후, SDS-PAGE로 단백질을 분리하고 PVDF 멤브레인으로 단백질을 이동시켰다. 5% 블록킹 버퍼로 블록킹을 수행한 후, 1차 항체로 NK1 수용체와 염증관련인자인 IL-6의 항체를 반응시키고, HRP가 붙어있는 2차 항체와 반응시킨 다음, ECL로 발색하여 X-ray film에 노출시킨 후 발현량을 분석하였다.Western blot: A mixture of Avertin and Butanol was injected into the abdominal cavity of the rat at 1200 -1500 mg/kg, and after anesthesia, cardiac perfusion with 0.9% saline solution was performed to remove blood and euthanasia, followed by perfusion fixation. made it The spinal cord (L3-5) at the level of the knee joint was removed. After disrupting the tissue with a protein elution solution, proteins were separated by SDS-PAGE and transferred to a PVDF membrane. After performing blocking with 5% blocking buffer, the NK1 receptor reacts with the antibody of IL-6, an inflammation-related factor, with the primary antibody, and with the secondary antibody with HRP attached, and then develops color with ECL and X-ray After exposure to film, the expression level was analyzed.
<실시예 1><Example 1>
L-732,138 투여에 따른 통증 경감 효과확인Confirmation of pain relief effect according to L-732,138 administration
<1-1> L-732,138의 관절강 내 투여에 따른 통증 경감 효과<1-1> Pain relief effect of intra-articular administration of L-732,138
L-732,138 약물의 통증 경감 및 치료 효과를 확인하기 위해, MIA로 유발된 만성관절통증 랫드 (흰쥐, 또는 백서) 모델을 대상으로 관절강 내로 L-732,138 약물(10μM)을 30μl 주입하고, 통증 평가 방법인 PWT(paw withdrawal threshold)을 통해 통증 경감 효과를 분석하였다.To confirm the pain relieving and therapeutic effect of L-732,138 drug, 30 μl of L-732,138 drug (10 μM) was injected into the joint cavity in a rat (white rat or white paper) model of chronic joint pain induced by MIA, and pain evaluation method The pain relief effect was analyzed through the paw withdrawal threshold (PWT).
분석 결과, L-732,138 약물의 관절강 내 투여로 인해 통증의 정도가 감소되는 것으로 나타났고, 특히 약물 주입 후, 9시간 후에 통증의 정도가 급격히 감소되는 것으로 나타났다. 구체적으로 약물 주입 전 pre 값 대비 통증 경감 효과의 비를 보여주는 MPE(Maxiaml possible effect)는 주입 9시간 후 약 46 %로 산출되었고, 이는 기존 통증의 46 %를 경감시켜 준다는 것을 의미한다. 또한 L-732,138 약물을 관절 강 내로 주입할 경우 통계적으로 주입 후 2일까지 약효가 지속되는 것으로 나타났다(도 1 참조).As a result of the analysis, it was found that the degree of pain was reduced due to intra-articular administration of the drug L-732,138, and in particular, the degree of pain was rapidly reduced 9 hours after drug injection. Specifically, MPE (Maximum Possible Effect), which shows the ratio of pain relieving effect to the pre-value before drug injection, was calculated to be about 46% 9 hours after injection, which means that 46% of the existing pain is relieved. In addition, when the L-732,138 drug was injected into the joint cavity, it was statistically shown that the drug effect lasted up to 2 days after injection (see FIG. 1).
<1-2> L-732,138의 척수강 내 투여에 따른 통증 경감 효과<1-2> Pain relief effect of intrathecal administration of L-732,138
MIA로 유발된 만성관절통증 랫드 (흰쥐, 또는 백서) 모델을 대상으로 척수강 내로 L-732,138 약물(10μM)을 10μl 주입하고, 통증 평가 방법인 PWT(paw withdrawal threshold)을 통해 통증 경감 효과를 분석하였다.10 μl of L-732,138 drug (10 μM) was injected intrathecally into the MIA-induced chronic joint pain rat (rat or white paper) model, and the pain relief effect was analyzed through the pain evaluation method PWT (paw withdrawal threshold). .
분석 결과, L-732,138 약물의 척수강 내 투여로 인해 통증의 정도가 감소되는 것으로 나타났고, 약물 주입 6시간 후에 통증 경감 효과가 가장 좋은 것으로 확인되었으며, 주입 전 pre 값 대비 통증 경감 효과의 비를 보여주는 MPE는 주입 6시간 후 약 63 %로 산출되었다. 이는 기존 통증의 63 %를 경감시켜 준다는 것을 의미한다. 또한 L-732,138 약물을 척수강 내로 주입할 경우 통계적으로 주입 후 3일까지 약효가 지속되는 것으로 확인되었다(도 2 참조).As a result of the analysis, intrathecal administration of the L-732,138 drug showed that the degree of pain was reduced, and it was confirmed that the pain relief effect was the best 6 hours after the drug injection, and the ratio of the pain relief effect compared to the pre-injection value was shown. MPE was calculated to be approximately 63% 6 hours after injection. This means that 63% of existing pain is relieved. In addition, when the L-732,138 drug was injected intrathecally, it was statistically confirmed that the drug effect lasted up to 3 days after injection (see FIG. 2).
이러한 결과를 통해 본 발명자들은 본 발명의 L-732,138 약물이 통증을 완화 및 경감시키는 효과가 있음을 알 수 있었고, 관절강 내로의 투여 및 척수강 내로의 투여 모두 통증 경감 효과를 보이는 것으로 나타났는데, 척수강 내로의 투여방법이 관절강 내로의 투여방법과 비교하여 통증 경감 효과가 더 우수한 것으로 나타났다.Through these results, the present inventors found that the L-732,138 drug of the present invention had an effect of alleviating and alleviating pain, and both intra-articular and intrathecal administration showed pain relieving effects. The administration method of was found to be more effective in reducing pain compared to the intra-articular administration method.
<실시예 2><Example 2>
L-732,138 투여량에 따른 통증 경감 효과확인Confirmation of pain relief effect according to L-732,138 dosage
본 발명자들은 상기 실시예 1을 통해 L-732,138 약물이 통증을 경감시키는 활성이 있음을 확인함으로써, 다음으로 약물 투여량에 따른 통증 경감 효과를 분석하였다.The present inventors confirmed that the drug L-732,138 has pain-reducing activity through Example 1, and then analyzed the pain-reducing effect according to the dose of the drug.
<2-1> L-732,138 투여량에 따른 관절강 내 투여 시 통증 경감 효과<2-1> Pain relief effect when administered intra-articularly according to the dose of L-732,138
MIA로 유발된 만성관절통증 랫드 (흰쥐, 또는 백서) 모델을 대상으로 관절강 내로 L-732,138 약물을 농도별(10μM, 1μM, 100nM)로 주입하고(30μl), 통증 평가 방법인 PWT(paw withdrawal threshold) 평가를 통해 통증 경감 효과를 분석하였다.L-732,138 drug was injected (30 μl) into the joint cavity at different concentrations (10 μM, 1 μM, 100 nM) in a rat (rat or white paper) model of chronic joint pain induced by MIA, and the pain evaluation method, PWT (paw withdrawal threshold) ), the pain relief effect was analyzed.
분석 결과, L-732,138 약물의 투여량에 비례하여 통증 경감 효과가 나타나는 것을 확인하였다. 구체적으로 L-732,138을 10 μM 주입 시, 최대 약 46 % 통증이 감소되는 것으로 나타났고, 그 효과는 통계적으로 주입 후 2일까지 지속되는 것으로 나타났으며, 1 μM 주입 시, 최대 약 27 % 통증을 줄여주며 그 효과는 통계적으로 주입 후 9시간까지 지속되는 것으로 나타났다. 이러한 결과를 토대로 L-732,138 약물의 관절강 내 투여에 따른 ED50(effective dose 50)은 4.49 μM인 것으로 나타났다(도 3 참조).As a result of the analysis, it was confirmed that the pain relieving effect appeared in proportion to the dose of L-732,138. Specifically, when L-732,138 was injected at 10 μM, pain was reduced by up to about 46%, and the effect was statistically shown to last up to 2 days after injection, and when injected with 1 μM, it was shown to reduce pain by up to about 27%. The effect was statistically shown to last up to 9 hours after injection. Based on these results, it was found that the effective dose 50 (ED50) according to the intra-articular administration of the drug L-732,138 was 4.49 μM (see FIG. 3).
<2-2> L-732,138 투여량에 따른 척수강 내 투여 시 통증 경감 효과<2-2> Pain relief effect when administered intrathecally according to the dose of L-732,138
MIA로 유발된 만성관절통증 랫드 (흰쥐, 또는 백서) 모델을 대상으로 척수강 내로 L-732,138 약물을 농도별(10μM, 1μM, 100μM)로 주입하고(10ul), 통증 평가 방법인 PWT(paw withdrawal threshold) 평가를 통해 통증 경감 효과를 분석하였다.In a rat (rat or white paper) model of chronic joint pain induced by MIA, L-732,138 drug was injected intrathecally at concentrations (10μM, 1μM, 100μM) (10ul), and the pain assessment method PWT (paw withdrawal threshold) ), the pain relief effect was analyzed.
분석 결과, 척수강 내로 L-732,138 약물 투여 시, 투여량에 비례하여 통증 경감 효과가 나타나는 것을 확인하였다. 구체적으로 10 μM 주입 시, 최대 약 63 % 통증이 감소되는 것으로 나타났고, 그 효과는 통계적으로 주입 후 3일까지 지속되는 것으로 나타났다. 1 μM 주입 시에는 최대 약 25 % 통증이 감소되며 그 효과는 통계적으로 주입 후 12시간까지 지속되는 것으로 나타났다. 이러한 결과를 토대로 L-732,138 약물의 척수강 내 투여에 따른 ED50(effective dose 50)은 1.68 μM인 것으로 나타났다(도 4 참조).As a result of the analysis, it was confirmed that when the L-732,138 drug was administered intrathecally, the pain relieving effect appeared in proportion to the dose. Specifically, at the time of 10 μM injection, it was found that pain was reduced by up to about 63%, and the effect was statistically shown to last up to 3 days after injection. When injected with 1 μM, pain was reduced by up to about 25%, and the effect was statistically shown to last up to 12 hours after injection. Based on these results, it was found that the effective dose 50 (ED50) of intrathecal administration of the drug L-732,138 was 1.68 μM (see FIG. 4).
이러한 결과를 통해 본 발명자들은 L-732,138 약물을 척수강 내로 투여할 경우, 관절강 내로 투여하는 경우에 비해 더 적은 농도에서 더 우수한 통증 경감 효과가 나타난다는 것을 확인함으로써, 척수강 내로의 투여방법이 관절강 내로의 투여 방법에 비해 더 효과적으로 통증을 완화 및 개선시킬 수 있다는 것을 알 수 있었다. Through these results, the present inventors confirmed that when the drug L-732,138 is administered intrathecally, a better pain relieving effect appears at a lower concentration than when administered into the joint cavity, so that the intrathecal administration method is It was found that it could alleviate and improve pain more effectively than the administration method.
<실시예 3><Example 3>
L-732,138 투여에 따른 통증 전달분자의 발현변화 분석Analysis of expression changes of pain transmitter molecules according to L-732,138 administration
본 발명자들은 앞서 실시예들의 실험을 통해 L-732,138 약물이 통증의 개선 및 완화 효과가 있음을 확인하였다. 이에 본 발명자들은 L-732,138 약물이 통증 관련 신호경로에 있어서, 통증전달 신경펩타이드인 CGRP(calcitonin gene-related peptide) 및 SP(susbstance P)의 발현을 조절할 수 있는지를 분석하였다.The present inventors confirmed that the drug L-732,138 has an effect of improving and alleviating pain through the experiments of the previous examples. Accordingly, the present inventors analyzed whether the L-732,138 drug could regulate the expression of pain transmission neuropeptides, CGRP (calcitonin gene-related peptide) and SP (susceptance P), in the pain-related signaling pathway.
이를 위해 MIA로 유발된 만성관절통증 랫드 (흰쥐, 또는 백서)의 관절강 및 척수강 내로 L-732,138을 각각 주입한 개체로부터 관절 활막을 분리한 후, CGRP와 SP의 발현수준을 분석하였다. 또한 이때 대조군으로는 L-732,138 대신 생리식염수 (saline)을 처리한 군을 사용하였다.To this end, joint synovial membranes were isolated from mice injected with L-732,138 into the articular and spinal cavities of rats (white rats or white papers) with chronic joint pain induced by MIA, respectively, and then the expression levels of CGRP and SP were analyzed. In addition, as a control group, a group treated with saline instead of L-732,138 was used.
그 결과, 도 5의 면역형광법 분석 결과에 나타낸 바와 같이, 대조군에 비해 L-732,138 약물을 투여한 개체의 관절 활막에서 CGRP와 SP의 발현 수준이 감소하는 것으로 나타났다.As a result, as shown in the immunofluorescence analysis results of FIG. 5 , the expression levels of CGRP and SP in the joint synovium of the subjects administered with the L-732,138 drug were decreased compared to the control group.
또한, 도 6의 면역조직화학법 분석 결과에 나타낸 바와 같이, 대조군에 비해 L-732,138 약물을 투여한 개체의 척수(dorsal horn의 substantia gelatinosa (larmina Ⅰ,Ⅱ))에서도 CGRP와 SP의 발현 수준이 감소하는 것으로 나타났다.In addition, as shown in the immunohistochemical analysis results of FIG. 6, the expression levels of CGRP and SP were also found in the spinal cord (substantia gelatinosa (larmina I, II) of the dorsal horn) of individuals administered with the L-732,138 drug compared to the control group. appeared to decrease.
이러한 결과를 통해 본 발명자들은 본 발명의 L-732,138 약물이 통증전달 물질인 CGRP와 SP의 발현을 감소시켜 통증을 완화 및 개선할 수 있음을 알 수 있었다.Through these results, the present inventors found that the L-732,138 drug of the present invention can alleviate and improve pain by reducing the expression of CGRP and SP, which are pain transmitters.
<실시예 4><Example 4>
L-732,138 투여에 따른 통증 전달 수용체 및 항염증성 사이토카인의 발현변화 분석Analysis of expression changes of pain receptors and anti-inflammatory cytokines according to L-732,138 administration
나아가 본 발명자들은 MIA로 유발된 만성관절통증 랫드 (흰쥐, 또는 백서)의 관절강 및 척수강 내로 L-732,138을 각각 주입한 개체의 척수에서 통증 전달 수용체인 NK-1( neurokinin-1) 수용체의 세포외부(extracellular)의 발현 수준과 항염증성 (anti-inflammatory) 사이토카인인 IL-6(interlukin-6)의 발현 수준을 분석하였다.Furthermore, the present inventors found that L-732,138 was injected into the joint cavity and spinal cord of rats (rats or white papers) suffering from chronic joint pain induced by MIA, respectively. (extracellular) expression levels and anti-inflammatory cytokine IL-6 (interlukin-6) expression levels were analyzed.
그 결과, 도 7에 나타낸 바와 같이, L-732,138을 관절강 내로 주입한 개체의 척수 dorsal ipsilateral에서 세포외부(extracellular)의 NK1 수용체의 발현은 대조군에 비해 감소되어 있는 것으로 나타났고, L-732,138을 척수강 내로 주입한 개체의 척수 dorsal ipsilateral에서는 세포외부(extracellular)의 NK1 수용체의 발현은 대조군에 비해 증가한 것으로 나타났다. 이는 척수강 내로 적용한 NK1 수용체 길항제가 NK1 수용체와 결합하여, 통증 신호 전달을 위한 NK1 수용체의 세포 내부로의 내재화(internalization)를 차단함으로써 SP-NK1의 세포내 신호 전달이 감소된 것으로 보여진다.As a result, as shown in FIG. 7, the expression of extracellular NK1 receptors in the spinal dorsal ipsilateral of the subject injected with L-732,138 into the joint cavity was reduced compared to the control group, and L-732,138 was injected into the spinal cavity. Expression of extracellular NK1 receptors in the spinal cord dorsal ipsilateral of the injected individuals was increased compared to the control group. This is because the NK1 receptor antagonist applied intrathecally binds to the NK1 receptor and blocks internalization of the NK1 receptor for pain signal transmission into cells, thereby reducing intracellular signal transmission of SP-NK1.
또한, 항염증성 (anti-inflammatory) 사이토카인인 IL-6(interlukin-6)의 발현수준 분석 결과, 대조군에 비해 L-732,138을 주입한 개체에서 IL-6의 발현이 증가한 것으로 나타났다.In addition, as a result of analyzing the expression level of IL-6 (interlukin-6), an anti-inflammatory cytokine, it was found that the expression of IL-6 increased in the subjects injected with L-732,138 compared to the control group.
이러한 결과를 통해, 본 발명자들은 본 발명의 L-732,138 약물이 통증 전달 신호를 조절하여 통증을 완화 및 감소시킬 수 있음을 알 수 있었고 동시에 항염증 활성도 가지고 있어 통증 및 염증을 함께 완화시킬 수 있다는 것을 알 수 있었다.Through these results, the present inventors found that the L-732,138 drug of the present invention can alleviate and reduce pain by regulating pain transmission signals, and at the same time, it has anti-inflammatory activity, so it can alleviate pain and inflammation together. Could know.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, the present invention has been looked at with respect to its preferred embodiments. Those skilled in the art to which the present invention pertains will be able to understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the equivalent scope will be construed as being included in the present invention.
Claims (10)
상기 조성물은 관절강 또는 척수강 내로 투여되는 것을 특징으로 하는, 통증의 예방 또는 치료용 약학적 조성물.According to claim 1,
The pharmaceutical composition for the prevention or treatment of pain, characterized in that the composition is administered into the joint cavity or spinal cavity.
상기 통증은 만성 통증(chronic pain)인 것을 특징으로 하는, 통증의 예방 또는 치료용 약학적 조성물.According to claim 1,
The pain is characterized in that chronic pain (chronic pain), a pharmaceutical composition for the prevention or treatment of pain.
상기 만성 통증은 신경병증성 통증, 복합부위 통증 증후군, 대상포진 후 신경통 및 척추 수술 후 통증 증후군으로 이루어진 군 중에서 선택되는 것을 특징으로 하는, 통증의 예방 또는 치료용 약학적 조성물.According to claim 3,
The chronic pain is a pharmaceutical composition for preventing or treating pain, characterized in that selected from the group consisting of neuropathic pain, complex regional pain syndrome, post-herpetic neuralgia and pain syndrome after spinal surgery.
상기 신경병증성 통증은 말초 신경 손상, 중추 신경 손상 및 염증성 신경 손상으로 이루어진 군으로부터 선택되는 1종 이상의 신경 손상에 의해서 유도되는 것을 특징으로 하는, 통증의 예방 또는 치료용 약학적 조성물.According to claim 4,
The neuropathic pain is characterized in that it is induced by one or more types of nerve damage selected from the group consisting of peripheral nerve damage, central nerve damage and inflammatory nerve damage, a pharmaceutical composition for preventing or treating pain.
상기 신경병증성 통증은 말초신경계 이상 또는 손상, 척수신경 손상을 포함한 다발성경화증, 척수부상, 통각과민, 감각과민, 신경병증, 당뇨성 신경장애, 신경염, 신경통, 작열통, 이질통, 포진후신경통, 요추 신경근압박, 암과 관련된 통증, 알코올 중독, 비정형 안면통증, 포진성 신경통, 중풍후통증, HIV 연관 신경병증, 골관절염 통증, 관절통증 및 환상사지통증으로 이루어진 군에서 선택되는 것을 특징으로 하는, 통증의 완화 또는 치료용 약학적 조성물.According to claim 4,
The neuropathic pain includes peripheral nervous system abnormality or damage, multiple sclerosis including spinal nerve injury, spinal cord injury, hyperalgesia, hyperesthesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, causalgia, allodynia, postherpetic neuralgia, lumbar spine of pain, characterized in that selected from the group consisting of nerve root compression, cancer-related pain, alcoholism, atypical facial pain, herpetic neuralgia, post-paralytic pain, HIV-associated neuropathy, osteoarthritis pain, joint pain and phantom limb pain A pharmaceutical composition for palliative or therapeutic use.
상기 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르 화합물은 SP(Substance P)/NK1(neurokinin 1)의 신호경로를 차단하는 활성을 통해 통증을 완화 또는 감소시키는 것을 특징으로 하는, 통증의 완화 또는 치료용 약학적 조성물.According to claim 1,
The N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester compound relieves or reduces pain through the activity of blocking the SP (Substance P)/NK1 (neurokinin 1) signaling pathway. Characterized in, a pharmaceutical composition for pain relief or treatment.
상기 N-아세틸-L-트립토판 3,5-비스(트리플루오로메틸)벤질 에스테르 화합물은 항염증성 사이토카인의 발현을 증가시키는 것을 특징으로 하는, 통증의 완화 또는 치료용 약학적 조성물.According to claim 1,
The N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl) benzyl ester compound is characterized by increasing the expression of anti-inflammatory cytokines, a pharmaceutical composition for pain relief or treatment.
상기 항염증성 사이토카인은 IL-6인 것을 특징으로 하는, 통증의 완화 또는 치료용 약학적 조성물.According to claim 8,
The anti-inflammatory cytokine is IL-6, characterized in that, a pharmaceutical composition for pain relief or treatment.
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| KR20160089378A (en) | 2013-11-26 | 2016-07-27 | 파마사이언스 인크. | Protein kinase inhibitors |
| KR102129114B1 (en) | 2018-07-26 | 2020-07-02 | 주식회사 온코파마텍 | A compound having TrkA inhibitory activity, and a pharmaceutical composition for preventing or treating pain containing the compound as an active ingredient |
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| KR20160089378A (en) | 2013-11-26 | 2016-07-27 | 파마사이언스 인크. | Protein kinase inhibitors |
| KR102129114B1 (en) | 2018-07-26 | 2020-07-02 | 주식회사 온코파마텍 | A compound having TrkA inhibitory activity, and a pharmaceutical composition for preventing or treating pain containing the compound as an active ingredient |
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