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(1R, 3S)-(-)-反式-PAT：一种新型的具有5-HT2A和5-HT2B受体反向激动剂/拮抗剂活性的全效血清素5-HT2C受体激动剂。

(1R, 3S)-(-)-trans-PAT: a novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity.

作者信息

Booth Raymond G, Fang Lijuan, Huang Yingsu, Wilczynski Andrzej, Sivendran Sashikala

机构信息

Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610-0485, United States.

出版信息

Eur J Pharmacol. 2009 Aug 1;615(1-3):1-9. doi: 10.1016/j.ejphar.2009.04.035. Epub 2009 May 3.

DOI:10.1016/j.ejphar.2009.04.035
PMID:19397907
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2749987/
Abstract

The serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) G protein-coupled receptors signal primarily through G alpha(q) to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT(2C) receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT(2C) agonists that do not also activate 5-HT(2A) or 5-HT(2B) receptors is challenging because transmembrane domain identity is about 75% among 5-HT(2) subtypes. This paper reports 5-HT(2) receptor affinity and function of (1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), a small molecule that produces anorexia and weight-loss after peripheral administration to mice. (-)-Trans-PAT is a stereoselective full-efficacy agonist at human 5-HT(2C) receptors, plus, it is a 5-HT(2A)/5-HT(2B) inverse agonist and competitive antagonist. The K(i) of (-)-trans-PAT at 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors is 410, 1200, and 37 nM, respectively. Functional studies measured activation of PLC/[(3)H]-IP formation in clonal cells expressing human 5-HT(2) receptors. At 5-HT(2C) receptors, (-)-trans-PAT is an agonist (EC(50) = 20 nM) comparable to serotonin in potency and efficacy. At 5-HT(2A) and 5-HT(2B) receptors, (-)-trans-PAT is an inverse agonist (IC(50) = 490 and 1,000 nM, respectively) and competitive antagonist (K(B) = 460 and 1400 nM, respectively) of serotonin. Experimental results are interpreted in light of molecular modeling studies indicating the (-)-trans-PAT protonated amine can form an ionic bond with D3.32 of 5-HT(2A) and 5-HT(2C) receptors, but, not with 5-HT(2B) receptors. In addition to probing 5-HT(2) receptor structure and function, (-)-trans-PAT is a novel lead regarding 5-HT(2C) agonist/5-HT(2A) inverse agonist drug development for obesity and neuropsychiatric disorders.

摘要

血清素5-HT(2A)、5-HT(2B)和5-HT(2C) G蛋白偶联受体主要通过Gα(q)信号转导来激活磷脂酶C（PLC）并形成肌醇磷酸（IP）和二酰基甘油。人类5-HT(2C)受体仅在中枢神经系统中表达，参与多种生理和心理过程。开发不同时激活5-HT(2A)或5-HT(2B)受体的5-HT(2C)激动剂具有挑战性，因为5-HT(2)亚型之间的跨膜结构域同一性约为75%。本文报道了(1R,3S)-(-)-反式-1-苯基-3-二甲基氨基-1,2,3,4-四氢萘（PAT）的5-HT(2)受体亲和力和功能，PAT是一种小分子，经外周给予小鼠后可产生厌食和体重减轻作用。(-)-反式-PAT是人类5-HT(2C)受体的立体选择性全效激动剂，此外，它还是5-HT(2A)/5-HT(2B)反向激动剂和竞争性拮抗剂。(-)-反式-PAT在5-HT(2A)、5-HT(2B)和5-HT(2C)受体上的K(i)分别为410、1200和37 nM。功能研究测定了表达人类5-HT(2)受体的克隆细胞中PLC/[(3)H]-IP形成的激活情况。在5-HT(2C)受体上，(-)-反式-PAT是一种激动剂（EC(50) = 20 nM），其效力和效能与血清素相当。在5-HT(2A)和5-HT(2B)受体上，(-)-反式-PAT是血清素的反向激动剂（IC(50)分别为490和1000 nM）和竞争性拮抗剂（K(B)分别为460和1400 nM）。根据分子模拟研究对实验结果进行了解释，该研究表明(-)-反式-PAT的质子化胺可与5-HT(2A)和5-HT(2C)受体的D3.32形成离子键，但不能与5-HT(2B)受体形成离子键。除了探究5-HT(2)受体的结构和功能外，(-)-反式-PAT还是肥胖症和神经精神疾病5-HT(2C)激动剂/5-HT(2A)反向激动剂药物开发的新型先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/d236bfcae552/nihms113545f7a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/386f441962ec/nihms113545f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/a60cc883e51b/nihms113545f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/08c232e3aeb0/nihms113545f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/2068e0fba865/nihms113545f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/5bebd632a123/nihms113545f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/fddd9bcad87a/nihms113545f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/d236bfcae552/nihms113545f7a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/386f441962ec/nihms113545f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/a60cc883e51b/nihms113545f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/08c232e3aeb0/nihms113545f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/2068e0fba865/nihms113545f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/5bebd632a123/nihms113545f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/fddd9bcad87a/nihms113545f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7431/2749987/d236bfcae552/nihms113545f7a.jpg

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