A novel pyrrolidine analog of histamine as a potent, highly selective histamine H3 receptor agonist.
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.
Shih
N Y
NY
Department of Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
Lupo
A T
AT
Aslanian
R
R
Orlando
S
S
Piwinski
J J
JJ
Green
M J
MJ
Ganguly
A K
AK
Clark
M A
MA
Tozzi
S
S
Kreutner
W
W
D006632:Histamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000737:chemistry*
D017442:Histamine Agonists; D011759:Pyrrolidines; D006632:Histamine; C032519:pyrrolidine