ChemInform Abstract: Ring-Substituted Histaprodifen Analogues as Partial Agonists for Histamine H1 Receptors: Synthesis and Structure-Activity Relationships.

Abstract

Abstract Thirteen racemic benzene ring-substituted analogues of histaprodifen ( 8a ; 2-[2-(3,3-diphenylpropyl)-1 H -imidazol-4-yl]ethanamine), a novel lead for potent and selective histamine H 1 -receptor agonists, have been prepared from substituted 4,4-diphenylbutyronitriles 5 via cyclization of the corresponding methyl butyrimidates 6 with 2-oxo-4-phthalimido-1-butyl acetate in liquid ammonia, followed by deprotection. Nitriles 5 were accessible by alkylation of either substituted diphenylmethanes with 3-bromopropionitrile or diethyl malonate with substituted 1-chloro-diphenylmethanes and subsequent standard reactions. The title compounds 8 displayed partial agonism on contractile H 1 receptors of the guinea-pig ileum ( E max = 2–98% relative to histamine) and, compared with the endogenous agonist, were endowed with agonist potencies of 4–92%. The meta fluorinated ( 8c ) and meta chlorinated ( 8f ) analogues showed the highest relative potency in this series (95% confidence limits 85–99% and 78–102%), but did not exceed the value of the lead 8a (99–124%). Compound 8c (2-[2-[3-(3-fluorophenyl)-3-phenylpropyl]-1 H -imidazol-4-yl]ethanamine) was a partial agonist at contractile H 1 receptors of the guinea-pig aorta (relative potency 154% vs. 100% for histamine) and at relaxation-mediating endothelial H 1 receptors of the rat aorta (relative potency 556% vs. 100% for histamine) and matched with the functional behaviour of 8a . Agonism observed for each compound was sensitive to blockade by the selective H 1 -receptor antagonist mepyramine (pA 2 ≈ 9 (guinea-pig) and pA 2 ≈ 8 (rat aorta)). All histaprodifen analogues 8 stimulated neither histaminergic H 2 /H 3 nor cholinergic M 3 receptors. They displayed only low to moderate affinity for these sites (H 2 : pD' 2 3 /M 3 : pA 2 1 -receptor agonist, viz. 2-phenylhistamine.