Signal transduction and functional selectivity of F15599, a preferential post‐synaptic 5‐HT 1A receptor agonist

• Published in: British journal of pharmacology Vol. 156; no. 2; pp. 338 - 353
• Main Authors: Newman‐Tancredi, A, Martel, J‐C, Assié, M‐B, Buritova, J, Lauressergues, E, Cosi, C, Heusler, P, Bruins Slot, L, Colpaert, FC, Vacher, B, Cussac, D
• Format: Journal Article
• Language: English
• Published: 01-01-2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2008.00001.x

Background and purpose: 
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.
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‐HT
1A
receptors in binding experiments and in [
35
S]‐GTPγS 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]‐GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5‐HT, more potently and efficaciously stimulated G
αi
than G
αo
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.
Conclusions and implications: 
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.