title: A novel pyrrolidine analog of histamine as a potent, highly selective histamine H3 receptor agonist.
abstract: Employing classical conformational analysis on a known H3 agonist, (R)-alpha-methylhistamine (1), a series of conformationally constrained H3 agonists were proposed and synthesized. Pyrrolidine (+/-)-4a, a compound proposed to mimic the anti-conformation of (R)-alpha-methylhistamine (1), was found to be a potent and selective H3 agonist. The pyrrolidine (+/-)-4a was resolved, and its (+) enantiomer, immepyr [(+)-4a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 550) than (R)-alpha-methylhistamine (1) (H3/H1 ratio = 17), the standard H3 agonist. In fact, no evidence of H1 activity was detected at doses of immepyr [(+)-4a] as high as 100 mg/kg i.v. This pyrrolidine, immepyr [(2R,3S)-(+)-4a], represents, to our knowledge, the first reported cyclic, conformationally restricted analog of histamine to possess selective in vivo H3 agonist activity.
authors.affiliation: Department of Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
authors.forename: N Y
authors.initials: NY
authors.lastname: Shih
authors.forename: A T
authors.initials: AT
authors.lastname: Lupo
authors.forename: R
authors.initials: R
authors.lastname: Aslanian
authors.forename: S
authors.initials: S
authors.lastname: Orlando
authors.forename: J J
authors.initials: JJ
authors.lastname: Piwinski
authors.forename: M J
authors.initials: MJ
authors.lastname: Green
authors.forename: A K
authors.initials: AK
authors.lastname: Ganguly
authors.forename: M A
authors.initials: MA
authors.lastname: Clark
authors.forename: S
authors.initials: S
authors.lastname: Tozzi
authors.forename: W
authors.initials: W
authors.lastname: Kreutner
mesh_terms: D006632:Histamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000737:chemistry*
chemical_list: D017442:Histamine Agonists; D011759:Pyrrolidines; D006632:Histamine; C032519:pyrrolidine