The 5-HT_2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT_2CR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues 6–41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands. PAM 11 was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HT_2AR. A combination of 11 with the SSRI sertraline increased the anorectic effect. Subchronic administration of 11 reduced food intake and body weight gain without causing CNS-related malaise. The behavior of compound 11 identified in this work supports the interest of a serotonin 5-HT_2CR PAM as a promising therapeutic approach for obesity.

中文翻译：

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肥胖的5-羟色胺5-HT _2C受体的正变构调节剂。

5-HT _2C R激动剂lorcaserin在临床上被批准用于肥胖症治疗，它引起重要的副作用，主要与亚型选择性有关。为了寻找作为更安全的减肥药的5-HT _2C R变构调节剂，使用ExviTech平台筛选了Vivia Biotech的化学文库。在合成的类似物6 – 41中对鉴定出的命中VA240进行结构修饰，得到化合物11（N -[（1-苄基-1 H-吲哚-3-基）甲基]吡啶-3-胺，VA012），其剂量依赖性增强血清素功效，没有明显的脱靶活性以及与血清素或其他正构配体的低结合竞争。PAM 11在抑制啮齿动物的摄食方面非常活跃，这一作用与5-HT _2A R的激活无关。11与SSRI舍曲林的组合增加了厌食作用。亚慢性给药11可减少食物摄入和体重增加，而不会引起中枢神经系统相关的不适。在这项工作中确定的化合物11的行为支持5-羟色胺5-HT _2C R PAM作为肥胖的一种有前途的治疗方法的兴趣。