Pharmacological profile of F15599, a highly selective serotonin 5-HT1A receptor agonist

Abstract

Serotonin 5-HT1A receptors are localized presynaptically in the raphe and postsynaptically in regions associated with control of mood and cognition. Here, the profile of F15599 was examined in models of 5-HT1A receptor activities both in vitro and in vivo. F15599 exhibited high affinity at 5-HT1A receptors in rat hippocampal membranes (pKi =8.5) and at h5-HT1A receptors in CHO cells (pKi=8.6). F15599 did not interact (<50% effect at 10 µM) with over 40 other targets. In models of h5-HT1A receptor-mediated signal transduction, F15599 activated [35S]GTPgS binding in membranes of C6 glial cells (Emax=72% relative to 10 µM 5-HT=100%, pEC50=6.4), inhibited cAMP accumulation in Hela cells (95%, 6.5) and stimulated ERK1/2 phosphorylation in CHO cells (98%, 8.0). In functional autoradiography experiments on rat brain sections, 100µM F15599 increased [35S]GTPgS labeling in brain regions expressing 5-HT1A receptors, including frontal and entorhinal cortex, lateral septum, hippocampus and raphe nuclei. Activation by F15599 in all these brain regions was abolished by co-incubation of sections with 10 µM WAY100635. F15599 potently abolished immobility in the forced swim test (FST; ED50=0.05 mg/kg po), an effect that was blocked by WAY100635. F15599 increased dopamine levels in medial prefrontal cortex of freely moving rats (ED50=0.03 mg/kg ip) but required higher doses (ED50=0.24 mg/kg ip) to decrease hippocampal 5-HT. Upon chronic treatment (14 days, osmotic pumps), only a high dose of F15599 (20 mg/kg/day) desensitized somatodendritic 5-HT1A receptors (i.e. reduced the response to a challenge dose of the 5-HT1A agonist, buspirone 10 mg/kg ip, on day 15). In other acute measures of 5-HT1A receptor activation, F15599 induced hypothermia (ED50=0.88 mg/kg po), increased plasma corticosterone (ED50=0.45 mg/kg po), induced lower lip retraction (ED50=0.33 mg/kg po) and elements of the 5-HT behavioral syndrome: forepaw treading (ED50=1.5 mg/kg po) and flat body posture (ED50=8.3 mg/kg po). In summary, F15599 is a high efficacy selective 5-HT1A agonist. F15599 reduced immobility in the FST, and increased dopamine levels in frontal cortex at doses lower than those that produce other effects of 5-HT1A activation. F15599 shows promise for amelioration of CNS disorders involving 5-HT1A receptor dysfunctions.