Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors.
The effects of FG5893 were evaluated by several different methods; rats were used as experimental animals. Receptor binding studies revealed that FG5893 (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxy lic acid methyl ester) binds with high affinity to both 5-HT1A (Ki = 0.7 nM) and 5-HT2A receptors (Ki = 4.0 nM) but has only low affinity for the 5-HT2C receptor (Ki = 170 nM). FG5893 dose dependently reduced body temperature, and this effect was inhibited by pretreatment with (+/-)-pindolol. FG5893 (0.1 mg/kg) significantly inhibited head twitch behaviour induced by DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and FG5893 was also a potent inhibitor of ultrasound vocalization in rat pups (0.3 mg/kg) and of a passive avoidance response (0.1 mg/kg) in mature animals. FG5893 inhibited the cage-leaving response and induced part 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 elicited corticosterone release and reduced the immobility time in the forced-swim test (1 mg/kg). Together, these data indicate that the mixed 5-HT1A receptor agonist/5-HT2A receptor antagonist FG5983 is a potent 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 passive avoidance response. At increased doses, FG5893 possessed an antidepressant-like property.
Albinsson
A
A
Kabi Pharmacia AB, Department of CNS Research, Malmö, Sweden.
Björk
A
A
Svartengren
J
J
Klint
T
T
Andersson
G
G
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009539:Nicotinic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013550:Swimming; D014828:Vocalization, Animal / Q000187:drug effects
D014151:Anti-Anxiety Agents; D009539:Nicotinic Acids; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C081594:FG 5893; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003345:Corticosterone