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J Med Chem. 1995 May 12;38(10):1593-9.

A novel pyrrolidine analog of histamine as a potent, highly selective histamine H3 receptor agonist.

Author information

1
Department of Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.

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.

PMID:
7752184
DOI:
10.1021/jm00010a003
[Indexed for MEDLINE]

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