PRECLINICAL PHARMACOLOGY OF FG5893 - A POTENTIAL ANXIOLYTIC DRUG WITHHIGH-AFFINITY FOR BOTH 5-HT1A AND 5-HT2A RECEPTORS

The effects of FG5893 were evaluated by several different methods; rat s were used as experimental animals. Receptor binding studies revealed that FG5893 ophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxylic acid m ethyl ester) binds with high affinity to both 5-HT1A (K-i = 0.7 nM) an d 5-HT2A receptors (K-i = 4.0 nM) but has only low affinity for the 5- HT2C receptor (K-i = 170 nM), FG5893 dose dependently reduced body tem perature, and this effect was inhibited by pretreatment with (+/-)-pin dolol. FG5893 (0.1 mg/kg) significantly inhibited head twitch behaviou r induced by DOI (1-(2,5-dimethoxy-4-iodaphenyl)-2-aminopropane) and F G5893 was also a potent inhibitor of ultrasound vocalization in rat pu ps (0.3 mg/kg) and of a passive avoidance response (0.1 mg/kg) in matu re animals. FG5893 inhibited the cage-leaving response and induced par t of the 5-HT behavioural syndrome, but only at very high doses (5 and 10 mg/kg, respectively). At increased doses (1 mg/kg), FG5893 also el icited corticosterone release and reduced the immobility time in the f orced-swim test (1 mg/kg). Together, these data indicate that the mixe d 5-HT1A receptor agonist/5-HT1A receptor antagonist FG5983 is a poten t stimulator of presynaptic 5-HT1A receptors but is less active at the postsynaptic site. FG5893 had potent anxiolytic-like effects both on separation-induced ultrasound vocalization in rat pups and on a passiv e avoidance response. At increased doses, FG5893 possessed an antidepr essant-like property.