title: Ring-substituted histaprodifen analogues as partial agonists for histamine H(1) receptors: synthesis and structure-activity relationships.
abstract: Thirteen racemic benzene ring-substituted analogues of histaprodifen (8a; 2-[2-(3,3-diphenylpropyl)-1H-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]-1H-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) approximately 9 (guinea-pig) and pA(2) approximately 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) < 5; H(3)/M(3): pA(2) < 6). With regard to the substitution pattern on the benzene ring, there was no correlation between the histaprodifen series and the corresponding derivatives of another selective H(1)-receptor agonist, viz. 2-phenylhistamine.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, D-14195, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Elz
authors.forename: K
authors.initials: K
authors.lastname: Kramer
authors.forename: C
authors.initials: C
authors.lastname: Leschke
authors.forename: W
authors.initials: W
authors.lastname: Schunack
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D003500:Cyclization; D005260:Female; D006632:Histamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000138:chemical synthesis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: C409476:2-(2-(3-(3-fluorophenyl)-3-phenylpropyl)-1H-imidazol-4-yl)ethanamine; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D011969:Receptors, Histamine H1; C118994:histaprodifen; D006632:Histamine; D011738:Pyrilamine