1. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1Areceptor agonist
- Author
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Adrian Newman-Tancredi, P. Heusler, L. Bruins Slot, M.B. Assié, Fc C. Colpaert, Bernard Vacher, Cristina Cosi, Emilie Lauressergues, Jean-Claude Martel, J. Buritova, and Didier Cussac
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Pyridines ,medicine.drug_class ,G protein ,Aminopyridines ,Prefrontal Cortex ,CHO Cells ,In Vitro Techniques ,Biology ,Binding, Competitive ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Cricetulus ,Piperidines ,Cricetinae ,Internal medicine ,Functional selectivity ,medicine ,Animals ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Neurotransmitter ,Receptor ,Pharmacology ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Serotonin 5-HT1 Receptor Agonists ,Rats ,Cell biology ,Pyrimidines ,Endocrinology ,nervous system ,chemistry ,Receptor, Serotonin, 5-HT1A ,Autoradiography ,5-HT1A receptor ,Serotonin ,Signal transduction ,Proto-Oncogene Proteins c-fos ,Research Paper ,Signal Transduction - Abstract
Background and purpose: Activation of post-synaptic 5-HT1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A receptor agonist. Experimental approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. Key results: F15599 was highly selective for 5-HT1A receptors in binding experiments and in [35S]-GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT1A receptors. In cell lines expressing h5-HT1A receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT1A 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 [35S]-GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gαi than Gαo activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5-HT1A receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.
- Published
- 2009