title: Characterization of Ro 04-6790 and Ro 63-0563: potent and selective antagonists at human and rat 5-HT6 receptors.
abstract: 1. This study describes the in vitro characterization of two potent and selective 5-HT6 receptor antagonists at the rat and human recombinant 5-HT6 receptor. 2. In binding assays with [3H]-LSD, 4-amino-N-(2,6 bis-methylamino-pyrimidin-4-yl)-benzene sulphonamide (Ro 04-6790) and 4-amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulphonamide (Ro 63-0563) had mean pKi values +/-s.e.mean at the rat 5-HT6 receptor of 7.35+/-0.04 and 7.83+/-0.01, respectively and pKi values at the human 5-HT6 receptor of 7.26+/-0.06 and 7.91+/-0.02, respectively. 3 .Both compounds were found to be over 100 fold selective for the 5-HT6 receptor compared to 23 (Ro 04-6790) and 69 (Ro 63-0563) other receptor binding sites. 4. In functional studies, neither compound had any significant effect on basal levels of cyclicAMP accumulation in Hela cells stably expressing the human 5-HT6 receptor, suggesting that the compounds are neither agonists nor inverse agonists at the 5-HT6 receptor. However, both Ro 04-6790 and Ro 63-0563 behaved as competitive antagonists with mean +/-s.e.mean pA2 values of 6.75+/-0.07 and 7.10+/-0.09, respectively. 5. In rats habituated to observation cages, Ro 04-6790 produced a behavioural syndrome similar to that seen following treatment with antisense oligonucleotides designed to reduce the expression of 5-HT6 receptors. This behavioural syndrome consisted of stretching, yawning and chewing. 6. Ro 04-6790 and Ro 63-0563 represent valuable pharmacological tools for the identification of 5-HT6 receptors in natural tissues and the study of their physiological function.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: A J
authors.initials: AJ
authors.lastname: Sleight
authors.forename: F G
authors.initials: FG
authors.lastname: Boess
authors.forename: M
authors.initials: M
authors.lastname: Bös
authors.forename: B
authors.initials: B
authors.lastname: Levet-Trafit
authors.forename: C
authors.initials: C
authors.lastname: Riemer
authors.forename: A
authors.initials: A
authors.lastname: Bourson
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000631:Aminopyridines / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011743:Pyrimidines / Q000134:cerebrospinal fluid* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012702:Serotonin Antagonists / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000262:Adenylyl Cyclases; D000631:Aminopyridines; D016376:Oligonucleotides, Antisense; D011743:Pyrimidines; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; C114164:4-amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide; D000096926:Benzenesulfonamides; C114163:Ro 4-6790; C097216:serotonin 6 receptor