TRPV1 길항제 구조활성 연구 : 2-(4-Methansulfonylaminophenyl) Propanamide 계 및 6-5 Fused Heterocyclic Urea/Propanamide 계 유도체 연구

Abstract

TRPV1(Transient Receptor Potential Vanilloid 1)은 통각 자극의 분자 매개체로써 무 수초 통각 감각 신경 섬유인 C-fiber 와 small A-delta fiber 에 발현하는 수용체이다. TRPV1은 다양한 외인성 인자(vanilloid such as Capsaicin and Resiniferatoxin, 42℃ 이상의 열 등)와 내인성 인자(낮은 pH, anandamide, arachidonic acid 대사체, bradykinin, ATP, NGF와 같은 pro-nociceptive 대사체 등)의 물리적, 화학적 자극에 의해 활성화 되는 비선택적인 양이온 채널이다. 특히 높은 Ca2+ 의 투과를 하여 이온 채널이 활성화 되고, 이 활성화는 세포 내에 Ca2+ 의 양이 증가되며 일차 감각 신경(primary sensory neurons)의 흥분을 야기 시켜 결국 통증을 인지하게 된다. TRPV1 수용체는 여러 조직의 신경 섬유에 존재하는데 DRG neuron 에 가장 많이 분포하며 척수에서도 발견되고 시상하부, 해마, 흑색질 등 뇌에서도 많이 분포되어 있으며 신장, 방광 등에서도 발견된다. TRPV1 수용체는 다양한 통증의 통합자로써 뿐만 아니라 통증의 전달과 modulation 의 역할이 알려지고 있으며, 이 작용을 길항하는 기전의 화합물들이 진통제로 개발되는 연구가 활발히 진행되고 있다. 더 나아가 선택적으로 중추신경계의 혈액 뇌관문(Blood Brain Barrier)에 통과가 가능한 TRPV1 수용체 길항제의 개발은 새로운 통증학적 치료로 기대되고 있다. 본 연구실은 2-(4-Methansulfonylaminophenyl) Propanamide 계열의 유도체들을 합성하여 TRPV1 길항효과를 갖는, 진통제로써 가능성 있는 약물을 찾는 연구를 수행하였다. 그리고 다국적 제약회사인 아보트 (Abbott Inc.) 사에서 도출한 화합물 ABT-102 의 A-region 인 indazole 의 구조변환을 하여 새로운 A-region 을 설계 하였다. 이 설계를 기초로 본 연구실은 A-region 에 다양한 6-5 Fused Heterocyclic 화합물을 (indole, benzimidazole, benzotriazole, benzoxazole, benzothiazole) 합성하였고, 구조-활성 관계를 연구하였다. 특히 6개의 화합물이 2 nM 이하의 강력한 TRPV1 antagonism 을 나타내었고, 진통제로써 가능성 있는 약물 후보 물질을 본 연구를 통해 발견하였다.

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in human, is encoded by the TRPV1 gene. TRPV1 is primarily expressed on, small myelinated and unmyelinated medium size, sensory neurons in dorsal root and trigeminal ganglia, where sensory neurons cluster. TRPV1 is a non-selective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are heat greater than 43 0C and capsaicin, the pungent compound in hot chili peppers and resiniferatoxin (RTX). The activiation of TRPV1 leads painful, burning sensation. Its endogenous activators include low pH (acidic conditions), the endocannabinoid anandamide, N-arachionyl dopamine. In addition TRPV1 activation can be potentiated by pro-nociceptive mediators such as bradykinin, ATP, NGF, and others. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system. TRPV1 receptors are also found in muscles, joints, the urinary bladder and kidneys. The functional activity of TRPV1 has been demonstrated, within the central nervous system, in the spinal cord and specific sites in the brain including the hypothalamus, cerebellum, locus coeruleus, periaqueductal grey and cortex. Activation of TRPV1 sets off an influx of calcium and sodium, ions which in turn initiates a cascade of events that result in memebrane depolarization, neuronal firing and transduction of neural impulses. TRPV1 phosphorylates as a response to several algesic agents, resulting in a lower threshold of channel activation. Some substances such as bradykinin, nerve growth factor and protons have been reprted to sensitize the TRPV1 receptor. Activation of TRPV1 results in the release of pro-nociceptive peptides, which decreases when treated with TRPV1 antagonists. In general, most channel antagonists bind in the pore region, interacting with residues from all four monomers of the tetrameric channe. The siginificant role of this receptor plays as the transmission and modulation of pain (nociception), as well as the integration of diverse painful stimuli. For this reason, the discovery of small molecule antagonists of TRPV1 has been the subject of intense investigations among many pain research groups. Further more recently, it was demonstrated that the analgesic profile of TRPV1 antagonists can be siginificantly broadened if the receptor blockade occurs both in the peripheral and in the central nervous system. Therefore, development of selective TRPV1 receptor antagonists with good CNS penetration presents an important opportunity to treat a variety of pathological pain states. For finding promising analgesic with excellent antagonism, studies are performed not only by desigining and synthesizing TRPV1 receptor ligands which have 2-(4-methasulfonyaminophenyl) propanamide and 6-5 fused heterochcylic at A-region, urea/propanamide at B-region, but also by introducing various substituent based on rational method.