Positive-allosteric modulation of the 5-HT2C receptor: implications for neuropsychopharmacology and neurotherapeutics.
Positive-allosteric modulation of the 5-HT2C receptor: implications for neuropsychopharmacology and neurotherapeutics.
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5-HT2C 受体的正变构调节：对神经精神药理学和神经治疗学的影响。
DOI：
10.1038/s41386-018-0190-x
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Cunningham,KathrynA
中科院分区：
文献类型：
--
作者：
Zhou,Jia;Cunningham,KathrynA
5-羟色胺（5-hydroxytryptamine; 5-HT）在20世纪50年代在哺乳动物大脑中被发现。我们现在认识到大脑5-HT通过与至少14种5-HT受体以及5-羟色胺再摄取转运蛋白结合来实现灵活而复杂的作用。5-HT 2C受体（5-HT 2CR）是一种G蛋白偶联受体（GPCR），与精神和神经系统疾病有关，包括焦虑症、抑郁症、精神分裂症和物质使用障碍以及肥胖症。内源性激动剂结合的正构5-HT 2CR位点是基于5-HT 2CR在控制进食、能量和葡萄糖稳态中的作用的肥胖症配体发现的主要靶标，产生了FDA批准用于体重减轻的首个同类5-HT 2CR激动剂氯卡色林（Belviq®）。虽然5-HT 2CR拮抗剂可能介导某些抗精神病药物（如氯氮平）的副作用，增加体重增加，但5-HT 2CR拮抗剂的开发一直在寻求用于治疗焦虑症和抑郁症。重要的是，选择性激动剂和拮抗剂具有先进的5-HT 2CR神经精神药理学知识。5-HT与5-HT 2CR的结合导致构象变化，催化多种第二信使效应物和G蛋白依赖性信号的扩散。变构调节剂是结合空间上不同的变构位点并改变受体构象以调节其与其他配体和/或信号转导分子的相互作用的配体[1]。相对于高度保守的正构结构域，预期在受体亚型中变构位点的序列差异更高。这种变构调节是可饱和的（当变构位点被完全占据时达到有限的幅度）和探针依赖性的（根据正构配体而变化），具有单独控制亲和力和功效的前景。正变构调节剂（PAM）或负变构调节剂（NAM）可以增强或抑制对正构激动剂的功能反应，而沉默的变构配体被认为在变构结合位点与PAM或NAM竞争。另外，变构配体可以是具有或不具有PAM或NAM活性的拮抗剂或激动剂（例如，ago-PAM，增强激动剂并显示内在功效的配体）。小分子5-HT 2CR PAM不会作为正构激动剂（如氯卡色林），而是作用于5-HT 2CR上的不同变构位点并增强正构配体的信号传导（图1）。第一个鉴定的5-HT 2CR PAM是脂肪酸油酰胺[2]，其缺乏对其他GPCR的选择性。2003年，化学文库筛选导致发现抗生素林可霉素的类似物PNU-69176 E作为选择性5-HT 2CR PAM [3]。2012年，Zhou及其同事优化了合成路线以生成PNU-69176 E及其非对映体[4]，我们最近设计、合成并表征了一系列新的化学实体作为选择性5-HT 2CR PAM [5]。几种分子在体外增强5-HT 2CR诱发的信号传导，而不显示5-HT 2CR功效或改变5-HT 2AR信号传导。在临床前自我给药模型中，CYD-1-79表现出有利的总体药代动力学特征，增强5-HT 2CR介导的行为，减弱冲动行为和对可卡因相关线索的敏感性。这一系列5-HT 2CR PAM通过发现5-HT 2CR PAM得到补充，该PAM抑制啮齿动物的食物摄入[6]。因此，发现新的5-HT 2CR神经探针和治疗剂的化学空间现在正在扩大到包括变构5-HT 2CR调节剂，提供...
Serotonin (5-hydroxytryptamine; 5-HT) was identified in the mammalian brain in the 1950s. We now recognize brain 5-HT to actualize flexible and complex actions directed by binding to at least 14 5-HT receptors as well as the serotonin reuptake transporter. The 5-HT2C receptor (5-HT2CR) is a G protein-coupled receptor (GPCR) that has been implicated in psychiatric and neurological disorders, including anxiety, depression, schizophrenia, and substance use disorders as well as obesity. The orthosteric 5-HT2CR site, at which the endogenous agonist binds, has been a primary target for ligand discovery for obesity based upon the role of 5-HT2CR in the control of feeding, energy and glucose homeostasis, yielding the first-in-class 5-HT2CR agonist lorcaserin (Belviq®) approved by the FDA for weight loss. While 5-HT2CR antagonism potentially mediates the side effect of some antipsychotics (eg, clozapine) to increase weight gain, the development of 5-HT2CR antagonists has been pursued for the treatment of anxiety disorders and depression. Importantly, selective agonists and antagonists have advanced knowledge of 5-HT2CR neuropsychopharmacology. Binding of 5-HT to the 5-HT2CR results in a conformational change that catalyzes the diffusion of multiple second messenger effectors and G protein-dependent signaling. An allosteric modulator is a ligand that binds to a spatially distinct allosteric site (s) and alters the receptor conformation to modulate its interaction with other ligands and/or signal transduction molecules [1]. Higher sequence divergence for allosteric sites is expected across receptor subtypes relative to the highly conserved orthosteric domain. Such allosteric modulation is saturable (comes to a finite magnitude when the allosteric site is fully occupied) and probe-dependent (varies dependent upon the orthosteric ligand) with the prospects for separate control of affinity and efficacy. A positive-(PAM) or negative-allosteric modulator (NAM) can enhance or inhibit the functional response to an orthosteric agonist, while silent allosteric ligands are suggested to compete with PAMs or NAMs at the allosteric binding site. Additionally, allosteric ligands can be antagonists or agonists with, or without, PAM or NAM activity (eg, ago-PAMs, ligands that potentiate agonists and display intrinsic efficacy). Small molecule 5-HT2CR PAMs would not act as an orthosteric agonists (as does lorcaserin), but instead act at distinct allosteric site (s) on the 5-HT2CR and potentiate signaling of an orthosteric ligand (Fig. 1). The first identified 5-HT2CR PAM was the fatty acid oleamide [2], which lacked selectivity against other GPCRs. In 2003, chemical library screening resulted in the discovery of an analogue of the antibiotic lincomycin, PNU-69176E, as a selective 5-HT2CR PAM [3]. In 2012, Zhou and colleagues optimized the synthetic route to generate PNU-69176E and its diastereomer [4], and we have recently designed, synthesized and characterized a series of new chemical entities as selective 5-HT2CR PAMs [5]. Several molecules potentiated 5-HT2CR-evoked signaling in vitro without displaying 5-HT2CR efficacy or altering 5-HT2AR signaling. CYD-1-79 exhibited a favorable overall pharmacokinetic profile, potentiated 5-HT2CR-mediated behaviors, and attenuated impulsive action and sensitivity to cocaine-associated cues in a preclinical self-administration model. This series of 5-HT2CR PAMs is complemented by the discovery of a 5-HT2CR PAM, which suppressed food intake in rodents [6]. Thus, the chemical space for discovery of novel 5-HT2CR neuroprobes and therapeutics is now expanding to include allosteric 5-HT2CR modulators, providing …