A NOVEL PYRROLIDINE ANALOG OF HISTAMINE AS A POTENT, HIGHLY SELECTIVE HISTAMINE H-3 RECEPTOR AGONIST

Employing classical conformational analysis on a known H-3 agonist, (R)-alpha-methylhistamine (1), a series of conformationally constrained H-3 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 H-3 agonist. The pyrrolidine (+/-)-4a was resolved, and its (+) enantiomer; immepyr [(+)-4a], showed a greater separation of H-3 and H-1 activities in vivo (H-3/H-1 ratio >> 550) than (R)-alpha-methylhistamine (1) (H-3/H-1 ratio = 17), the standard H-3 agonist. In fact, no evidence of H-1 activity was detected at doses of immepyr [(+)-4a] as high as 100 mg/kg iv. This pyrrolidine, immepyr [(2R,3S)-(+)-4a], represents, to our knowledge, the first reported cyclic, conformationally restricted analog of histamine to possess selective in vivo H-3 agonist activity.