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Synthesis of Potent Non‐imidazole Histamine H 3 ‐Receptor Antagonists
Author(s) -
Ganellin C. Robin,
Leurquin Fabien,
Piripitsi Antonia,
Arrang JeanMichel,
Garbarg Monique,
Ligneau Xavier,
Schunack Walter,
Schwartz JeanCharles
Publication year - 1998
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199812)331:12<395::aid-ardp395>3.0.co;2-7
Subject(s) - imidazole , histamine , histamine h3 receptor , pyrrolidine , chemistry , stereochemistry , ed50 , antagonist , amine gas treating , in vivo , receptor , pharmacology , biochemistry , organic chemistry , biology , microbiology and biotechnology
Histamine has been converted into a non‐imidazole H 3 ‐receptor histamine antagonist by addition of a 4‐phenylbutyl group at the N α ‐position followed by removal of the imidazole ring. The resulting compound, N ‐ethyl‐ N ‐(4‐phenylbutyl)amine, remarkably has a K i = 1.3 μM as an H 3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure‐activity studies furnished N ‐(5‐phenoxypentyl)pyrrolidine ( K i = 0.18 ± 0.10 μM, for [ 3 H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo . Substitution of NO 2 into the para position of the phenoxy group gave N ‐(5‐ p ‐nitrophenoxypentyl)pyrrolidine, UCL 1972 ( K i = 39 ± 11 nM), ED 50 = 1.1 ± 0.6 mg/kg per os in mice on brain tele ‐methylhistamine levels.