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- Title
Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist.
- Authors
Newman-Tancredi, A.; Martel, J.-C.; Assi, M.-B.; Buritova, J.; Lauressergues, E.; Cosi, C.; Heusler, P.; Bruins Slot, L.; Colpaert, F. C.; Vacher, B.; Cussac, D.; Assié, M-B
- 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. Mandarin translation of abstract
- Subjects
MESSENGER RNA; PREFRONTAL cortex; CHEMICAL reactions; FRONTAL lobe; CELL lines
- Publication
British Journal of Pharmacology, 2009, Vol 156, Issue 2, p338
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1111/j.1476-5381.2008.00001.x