Signal transduction and functional selectivity of F15599, a preferential post‐synaptic 5‐HT_1A receptor agonist

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. ]-GTPgS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gai than Gao 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.

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

“…In contrast, a recently reported and efficacious 5-HT 1A receptor agonist, 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin-1-yl]methanone (F15599), exhibits more than 1000-fold selectivity for 5-HT1 A receptors versus all other sites examined (Newman-Tancredi et al, 2009) and displays a distinctive preferential agonist activity at cortical 5-HT 1A sites. Indeed, F15599 preferentially activates immediate early gene (c-fos) expression in rat frontal cortex, while eliciting little or no activation in hippocampus or medial or dorsal raphe (Newman-Tancredi et al, 2009). In addition, F15599 stimulated the electrical activity of pyramidal neurons in frontal cortex at low doses (0.2 g/kg i.v.…”

Radiosynthesis and Preclinical Evaluation of 18F-F13714 as a Fluorinated 5-HT1A Receptor Agonist Radioligand for PET Neuroimaging

“…Indeed, coimmunoprecipitation studies have indicated that 5-HT 1A receptors preferentially couple to distinct G-protein subtypes in different brain regions: G i in the dorsal raphe and other G-protein subtypes in other brain regions (38). Correspondingly, it has previously been shown that F13714 exhibited a distinctive signal transduction signature in vitro (39), leading to a preferential activation of presynaptic versus postsynaptic 5-HT 1A receptors. Thus, it is hypothesized that the capacity of agonist radiotracers to label 5-HT 1A receptors in different brain regions is associated with preferential interactions at receptors that couple to different Gprotein subtypes.…”

“…Taken together, the differences observed here in the labeling patterns of comparison of 18 F-F13714 and 18 F-F15599 provide further evidence that these agonists distinguish 5-HT 1A receptor subpopulations in different brain areas. We are confident that the radiopharmacologic profile of 18 F-F13714 will be appropriate for clinical studies, taking into account its wellcharacterized pharmacology (27,30,39). A quantitative approach using kinetic models is now needed to complete this work.…”

Activation of Dorsal Raphe Serotonin Neurons Is Necessary for Waiting for Delayed Rewards

“…For example, in the 5-choice serial reaction time task (5-CSRTT), Carli and Samanin (2000) combined a systemic dose of 8-OH-DPAT and dorsal raphe injection of the 5-HT 1A antagonist WAY 100635 to show that some of the effects of 8-OH-DPAT (slowing of responding and increased errors of omission) depend on the stimulation of postsynaptic 5-HT 1A receptors. Assié and colleagues compared the effects of the highly selective postsynaptic 5-HT 1A receptor agonist F15599 and the nonselective agonist F13714 and showed different relative effects on antidepressant-like activity (immobility in the forced swimming test) and 5-HT syndrome (forepaw treading and flat body posture) (Newman-Tancredi et al, 2009;Assié et al, 2010). These results suggest that the local application of 5-HT 1A receptor agonist is desirable to activate presynaptic 5-HT 1A receptors without affecting postsynaptic 5-HT 1A receptors.…”