Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT1A receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca2+ mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT1A receptor affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, serotonin 5-HT2A, histamine H1, and muscarinic M1 receptors, and favorable druglike properties (CNS-MPO, Fsp3, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT1A receptor-biased agonists could constitute promising antidepressant drug candidates.

中文翻译：

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1-（1-苯甲酰基哌啶丁-4-基）甲胺的新型芳氧基乙基衍生物作为细胞外调节激酶1/2（ERK1 / 2）磷酸化的首选5-羟色胺5-HT1A受体-激动剂，具有强大的抗抑郁样活性。

新型的1-（1-苯甲酰基哌啶-4-基）甲胺衍生物被设计为5-羟色胺5-HT1A受体的“偏向激动剂”。在信号转导分析（ERK1 / 2磷酸化，cAMP抑制，Ca2 +动员和β-arrestin募集）中测试了这些化合物，这些化合物鉴定出了ERK1 / 2磷酸化优先的芳氧基乙基衍生物。该新系列药物显示出较高的5-HT1A受体亲和力，相对于去甲肾上腺素α1，多巴胺D2、5-羟色胺5-HT2A，组胺H1和毒蕈碱M1受体具有> 1000倍的选择性，并具有良好的类药物特性（CNS-MPO，Fsp3，LELP）。铅结构（3-氯-4-氟苯基）（4-氟-4-（（（（2-（吡啶-2-基氧基）乙基）氨基）甲基）哌啶-1-基）甲酮（17，NLX- 204），在SafetyScreen44面板（包括hERG通道）中显示出高选择性，高溶解度，代谢稳定性，和Caco-2渗透，并且不阻断CYP3A4，CYP2D6同工酶或P-糖蛋白。初步的体内研究证实了其有希望的药代动力学特征。17还强烈刺激了大鼠皮层中的ERK1 / 2磷酸化，并显示出强效（MED = 0.16 mg / kg）和有效的抗抑郁剂样活性，完全消除了大鼠Porsolt试验中的固定性。这些数据表明，目前的5-HT1A受体偏向激动剂可以构成有希望的抗抑郁药候选物。完全消除了大鼠Porsolt测试中的固定性。这些数据表明，目前的5-HT1A受体偏向激动剂可以构成有希望的抗抑郁药候选物。完全消除了大鼠Porsolt测试中的固定性。这些数据表明，目前的5-HT1A受体偏向激动剂可以构成有希望的抗抑郁药候选物。