An impaired signaling capacity of the serotonin (5-HT) 5-HT_2C receptor (5-HT_2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT_2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT_2CR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT_2CR but not the 5-HT_2AR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT_2CR structure. Compound 16 modulated 5-HT_2CR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT_2CR agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.

中文翻译：

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设计，合成和表征的4-十一烷基哌啶-2-羧酰胺作为5-羟色胺（5-HT）5-HT _2C受体的正构构调节剂。

血清素（5-HT）5-HT _2C受体（5-HT _2C R）的信号传导能力受损，与促进可卡因使用障碍（CUD）复发易感性的神经行为过程有关。通过积极的变构调节恢复5-HT _2C R信号减弱提出了一种新颖的治疗方法。设计，合成并用药理学评估了几种带有4-烷基哌啶-2-羧酰胺骨架的新分子，从而发现了选择性5-HT _2C R阳性变构调节剂（PAM）。化合物16（CYD-1-79）增强了稳定表达人5-HT _2C R但不表达5-HT的细胞中5-HT诱发的细胞内钙释放_2A R细胞。基于新近解决的5-HT _2C R结构，确定了一个地形上独特的变构位点。化合物16调节了5-HT _2C R介导的自发运动，部分替代了5-HT _2C R激动剂WAY163909的训练剂量，与低剂量的WAY163909协同作用以完全替代WAY163909的刺激作用，并降低了复发易感性在啮齿动物自我给药模型中评估，表明其对CUD的治疗前景。