Newman-Tancredi A, Martel J-C, Assié M-B, Buritova J, Lauressergues E, Cosi C, Heusler P, Bruins Slot L, Colpaert F C, Vacher B, Cussac D
Neurobiology 2 Division, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, Castres, France.
Br J Pharmacol. 2009 Jan;156(2):338-53. doi: 10.1111/j.1476-5381.2008.00001.x. Epub 2009 Jan 12.
Activation of post-synaptic 5-HT(1A) receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT(1A) receptor agonist.
F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo.
F15599 was highly selective for 5-HT(1A) receptors in binding experiments and in [(35)S]-GTPgammaS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT(1A) receptors. In cell lines expressing h5-HT(1A) receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT(1A) receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [(35)S]-GTPgammaS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated G(alphai) than G(alphao) activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT(1A) receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT(1A) receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT(1A) receptors in vivo almost as potently as F13714.
F15599 showed a distinctive activation profiles for 5-HT(1A) receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT(1A) receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.
突触后 5-羟色胺（5-HT）1A 受体的激活可能为抑郁症提供更有效的治疗方法。我们描述了一种新型 5-HT1A 受体激动剂 F15599 的信号转导特征。
在体外和体内信号转导模型中，将 F15599 与化学同类物 F13714 以及（+）8-羟基二丙胺基四氢萘（+）8-OH-DPAT 进行比较。
在结合实验以及大鼠脑的[35S] - 鸟苷-5'-三磷酸γ-硫酯（[35S]-GTPγS）放射自显影中，F15599 对 5-HT1A 受体具有高度选择性，F15599 增加了表达 5-HT1A 受体区域的标记。在表达人 5-HT1A 受体的细胞系中，与 G 蛋白激活、人 5-HT1A 受体的内化或环磷酸腺苷（cAMP）积累的抑制相比，F15599 更有效地刺激细胞外信号调节激酶（ERK1/2）磷酸化。F13714、（+）8-OH-DPAT 和 5-HT 对这些反应的效价顺序不同。F15599 在额叶皮质比中缝核更有效地刺激[35S]-GTPγS 结合。与 5-HT 不同，F15599 更有效且有力地刺激 Gαi 而非 Gαo 的激活。在大鼠前额叶皮质（一个表达突触后 5-HT1A 受体的区域）中，F15599 有力地激活 ERK1/2 磷酸化并强烈诱导 c-fos 信使核糖核酸（mRNA）表达。相比之下，在中缝核区域（表达突触前 5-HT1A 受体），F15599 仅微弱诱导或不诱导 c-fos mRNA 表达。最后，尽管其在体外亲和力较低，但 F15599 在体内与 5-HT1A 受体的结合几乎与 F13714 一样有效。
F15599 显示出与参考激动剂不同的 5-HT1A 受体介导的信号通路激活特征，这与 5-HT1A 受体的功能选择性一致。在大鼠中，F15599 有力地激活前额叶皮质中的信号传导，这一特征可能是其在抑郁症和认知模型中产生有益作用的基础。
