title: Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: a comparison with diazepam and buspirone.
abstract: Hyperfunction of brain 5-hydroxytryptamine(2C) (5-HT(2C)) receptor is suggested to be involved in anxiety as evidenced by the fact that a putative 5-HT(2C) 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-HT(2C) 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-HT(2C) receptor (K(i): 1.10 nM) and high selectivity over 5-hydroxytryptamine(2A) (5-HT(2A)) receptor (K(i): 386 nM) and many other transmitter receptors. FR260010 showed antagonist activity at human 5-HT(2C) receptor in an intracellular calcium assay and showed no detectable intrinsic activity. The compound dose-dependently inhibited the hypolocomotion (ID(50): 1.89 mg/kg, p.o.) and hypophagia (ID(50): 2.84 mg/kg, p.o.) in rats induced by m-CPP, putative indices of brain 5-HT(2C) 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-HT(2C) receptor, and may have therapeutic potential for treatment of anxiety, with more desirable profiles than benzodiazepines or 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonists.
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305 -8585, Japan. katsuya.harada@jp.astellas.com
authors.forename: Katsuya
authors.initials: K
authors.lastname: Harada
authors.forename: Masaki
authors.initials: M
authors.lastname: Aota
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Inoue
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Matsuda
authors.forename: Takuma
authors.initials: T
authors.lastname: Mihara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamaji
authors.forename: Koji
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents; D002065:Buspirone / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology; D006224:Cricetinae; D003975:Diazepam / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D006591:Hexobarbital / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007398:Interpersonal Relations; D008297:Male; D008698:Mesylates / Q000493:pharmacokinetics / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D050479:Neurotransmitter Transport Proteins / Q000378:metabolism; D010879:Piperazines; D004856:Postural Balance / Q000187:drug effects; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D008698:Mesylates; C515915:N-(-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6-dihydrobenzo(h)quinazolin-4-amine dimethanesulfonate; D050479:Neurotransmitter Transport Proteins; D010879:Piperazines; D011799:Quinazolines; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D000431:Ethanol; D006591:Hexobarbital; D003975:Diazepam; C015068:1-(3-chlorophenyl)piperazine; D002118:Calcium; D002065:Buspirone