Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: A comparison with diazepam and buspirone

Hyperfunction of brain 5-hydroxytryptamine2C (5-HT2C) receptor is suggested to be involved in anxiety as evidenced by the fact that a putative 5-HT2C receptor agonist 1-(m-chlorophenyl)-piperazine (m-CPP) causes anxiety in humans. We have recently identified FR260010 (N-[3-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6-dihydrobenzo[h]quinazolin-4-amine dimethanesulfonate) as novel 5-HT2C receptor antagonist from diaryl amine derivatives, and here characterized in vitro and in vivo profiles of the compound. FR260010 showed high affinity for human 5-HT2C receptor (Ki: 1.10 nM) and high selectivity over 5-hydroxytryptamine2A (5-HT2A) receptor (Ki: 386 nM) and many other transmitter receptors. FR260010 showed antagonist activity at human 5-HT2C receptor in an intracellular calcium assay and showed no detectable intrinsic activity. The compound dose-dependently inhibited the hypolocomotion (ID50: 1.89 mg/kg, p.o.) and hypophagia (ID50: 2.84 mg/kg, p.o.) in rats induced by m-CPP, putative indices of brain 5-HT2C receptor antagonist activity. We then compared the effects of FR260010 with those of two other anxiolytics belonging to different classes, diazepam and buspirone, in anxiety models in rats and mice and adverse effect tests in mice. FR260010 (0.1–3.2 mg/kg, p.o.) and diazepam (1–10 mg/kg, p.o.) decreased behavioral indices of anxiety in all models, whereas buspirone (0.32–10 mg/kg, p.o.) did not significantly affect them in any models. In adverse effect tests, FR260010 and buspirone showed modest effects, whereas diazepam showed significant effects in all tests. These results suggest that FR260010 is a novel, potent, orally active and brain penetrable antagonist of 5-HT2C receptor, and may have therapeutic potential for treatment of anxiety, with more desirable profiles than benzodiazepines or 5-hydroxytryptamine1A (5-HT1A) receptor agonists.