A novel pyrrolidine analog of histamine as a potent, highly selective histamine H3 receptor agonist.
J Med Chem
; 38(10): 1593-9, 1995 May 12.
Article
em En
| MEDLINE
| ID: mdl-7752184
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
/
Histamina
/
Agonistas dos Receptores Histamínicos
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
1995
Tipo de documento:
Article
País de afiliação:
Estados Unidos