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 t...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-05, Vol.38 (10), p.1593-1599
Main Authors: Shih, Neng-Yang, Lupo, Andrew T, Aslanian, Robert, Orlando, Steven, Piwinski, John J, Green, Michael J, Ganguly, Ashit K, Clark, Michael A, Tozzi, Salvatore
Format: Article
Language:English
Subjects:
Biological and medical sciences
Histamine - analogs & derivatives
Histamine - chemistry
Histamine - pharmacology
Histamine Agonists
Medical sciences
Miscellaneous
Molecular Conformation
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Pyrrolidines - chemistry
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00010a003