title: Neuroendocrine evidence that (S)-2-(chloro-5-fluoro-indol- l-yl)-1-methylethylamine fumarate (Ro 60-0175) is not a selective 5-hydroxytryptamine(2C) receptor agonist.
abstract: The 5-hydroxytryptamine(2A) and (2C) (5-HT(2A) and 5-HT(2C)) receptors are so closely related that selective agonists have not been developed until recently with the advent of (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine fumarate (Ro 60-0175), a putatively selective 5-HT(2C) receptor agonist. In the present study, Ro 60-0175 was used to analyze the importance of 5-HT(2C) receptors in hormone secretion. Injection of Ro 60-0175 (5 mg/kg s.c.) produced a maximum increase in plasma levels of adrenocorticotrophic hormone, oxytocin, and prolactin at 15 min postinjection and a maximum increase in plasma corticosterone levels at 60 min postinjection. Ro 60-0175-mediated increases in plasma hormone levels were dose-dependent (corticosterone ED(50) = 2.43 mg/kg; oxytocin ED(50) = 4.19 mg/kg; and prolactin ED(50) = 4.03 mg/kg). To assess the role of 5-HT(2C) and 5-HT(2A) receptors in mediating the hormone responses to Ro 60-0175, rats were pretreated with the 5-HT(2C) antagonist 6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbonyl] indoline (SB 242084) or 5-HT(2A) antagonists (+/-)-2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol] (MDL 100,907) before injection of Ro 60-0175 (5 mg/kg s.c.). Neither SB 242084 (0.1, 0.5, 1, and 5 mg/kg i.p.) nor MDL 100,907 (1, 5, and 10 microg/kg s.c.) significantly inhibited the Ro 60-0175-induced increases in plasma hormone levels. The data suggest that Ro 60-0175 increases hormone secretion by mechanisms independent of the activation of 5-HT(2C) and/or 5-HT(2A) receptors and suggest that Ro 60-0175 is not a highly selective 5-HT(2C) receptor agonist.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Damjanoska
authors.forename: N A
authors.initials: NA
authors.lastname: Muma
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: D N
authors.initials: DN
authors.lastname: D'Souza
authors.forename: F
authors.initials: F
authors.lastname: Garcia
authors.forename: G A
authors.initials: GA
authors.lastname: Carrasco
authors.forename: G H
authors.initials: GH
authors.lastname: Kindel
authors.forename: K A
authors.initials: KA
authors.lastname: Haskins
authors.forename: M
authors.initials: M
authors.lastname: Shankaran
authors.forename: B R
authors.initials: BR
authors.lastname: Petersen
authors.forename: L D
authors.initials: LD
authors.lastname: Van De Kar
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005021:Ethylamines; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C079049:volinanserin