Biased agonism (or ”functional selectivity”) at G-protein-coupled receptors has attracted rapidly increasing interest as a means to improve drug discovery of more efficacious and safer pharmacotherapeutics. However, most studies are limited to in vitro tests of cellular signaling and few biased agonists have progressed to in vivo testing. As concerns 5-HT_1A receptors, which exert a major control of serotonergic signaling in diverse CNS regions, study of biased agonism has been limited by poor target selectivity and partial agonism of classically available ligands. However, a new generation of highly selective, efficacious and druggable agonists has advanced the study of biased agonism at this receptor and created therapeutic opportunities. The novel agonists show differential properties for G-protein signaling, cellular signaling (particularly pERK), electrophysiological effects, neurotransmitter release, neuroimaging by PET and pharmacoMRI, and behavioral tests of mood, motor activity and side effects. Overall, NLX-101 (a.k.a. F15599) exhibits preferential activation of cortical and brain stem 5-HT_1A receptors, whereas NLX-112 (a.k.a. befiradol or F13640) shows prominent activation of 5-HT_1A autoreceptors in Raphe nuclei and in regions associated with motor control. Accordingly, NLX-101 is potently active in rodent models of depression and respiratory control, whereas NLX-112 shows promising activity in models of Parkinson's disease across several species – rat, marmoset and macaque. Moreover, NLX-112 has also been labeled with ¹⁸F to produce the first agonist PET radiopharmaceutical (known as [¹⁸F]-F13640) for investigation of the active state of 5-HT_1A receptors in rodent, primate and human. The structure-functional activity relationships of biased agonists have been investigated by receptor modeling and novel compounds have been identified which exhibit increased affinity at 5-HT_1A receptors and new profiles of cellular signaling bias, notably for β-arrestin recruitment versus pERK. Taken together, the data suggest that 5-HT_1A receptor biased agonists constitute potentially superior pharmacological agents for treatment of CNS disorders involving serotonergic mechanisms.

G 蛋白偶联受体的偏向激动（或“功能选择性”）作为一种改进药物发现的更有效和更安全的药物治疗的手段，引起了越来越多的兴趣。然而，大多数研究仅限于细胞信号传导的体外测试，很少有偏向的激动剂进展到体内测试。至于 5-HT _1A受体在不同的 CNS 区域中对 5-羟色胺能信号传导发挥主要控制作用，但偏向激动的研究受到了传统配体的低靶选择性和部分激动的限制。然而，新一代的高选择性、有效和可成药的激动剂推进了对该受体偏向激动的研究，并创造了治疗机会。新型激动剂在 G 蛋白信号传导、细胞信号传导（尤其是 pERK）、电生理效应、神经递质释放、PET 和药物 MRI 的神经成像以及情绪、运动活动和副作用的行为测试方面显示出不同的特性。总体而言，NLX-101（又名 F15599）表现出优先激活皮质和脑干 5-HT _1A受体，而 NLX-112（又名 befiradol 或 F13640）在中缝核和与运动控制相关的区域中显示出 5-HT _{1A自身受体的显着激活。}因此，NLX-101 在啮齿动物的抑郁症和呼吸控制模型中具有强大的活性，而 NLX-112 在多个物种（大鼠、狨猴和猕猴）的帕金森病模型中显示出有希望的活性。此外，NLX-112 还被标记为¹⁸ F 以生产第一个激动剂 PET 放射性药物（称为 [ ¹⁸ F]-F13640），用于研究 5-HT _{1A的活性状态}啮齿动物、灵长类动物和人类的受体。已经通过受体模型研究了偏向激动剂的结构-功能活性关系，并且已经鉴定出对 5-HT _1A受体表现出增加的亲和力和细胞信号偏向性的新谱的新化合物，特别是对于 β-抑制蛋白募集与 pERK。总之，数据表明偏向 5-HT _1A受体的激动剂构成了用于治疗涉及 5-羟色胺能机制的 CNS 疾病的潜在优越药理学试剂。