F15599 is a novel agonist with high selectivity and efficacy at
serotonin 5-HT(1A) receptors (5-HT(1A)Rs). In signal transduction, electrophysiological and neurochemical tests,
F15599 preferentially activates post-synaptic 5-HT(1A)Rs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for
mood disorders. The in-vivo effects of
F15599 were therefore compared with those of a related compound,
F13714, in rat models of
antidepressant activity and 5-HT(1A)R activation: forced swimming test (FST), conditioned stress-induced ultrasonic vocalization,
5-HT syndrome, plasma
corticosterone and body temperature. Acute administration of
F15599 or
F13714 reduced immobility in the FST at low doses; these effects were long lasting and the effects of
F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of
F15599 were required to induce lower lip retraction, elements of the
5-HT behavioural syndrome,
hypothermia and to increase plasma
corticosterone levels. Notably, there was a greater separation of ED50 between FST and other effects for
F15599 than for
F13714. Thus, the in-vivo potency of
F15599 in models of
antidepressant/anti-stress activity is similar to that of
F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast
F15599 has a lower propensity than
F13714 to induce other serotonergic signs. The distinctive pharmacological profile of
F15599 suggests that preferential targeting of post-synaptic 5-HT(1A)Rs constitutes a promising strategy for improved
antidepressant therapy.