title: Structure-activity relationships of histamine H2-agonists, a new class of positive inotropic drugs.
abstract: The cimetidine-like moiety in impromidine was replaced by either alternative partial structures known from H2-antagonists or by H2-nonspecific lipophilic groups. The most potent H2-agonists were found in a series of compounds structurally derived from the H1-antagonist pheniramine. Arpromidine (N1-[3-(4-fluorophenyl)-3-(2-pyridinyl)propyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) may be considered a new lead for the development of "cardiohistaminergics". This guanidine combines both about 100 times the potency of histamine in the isolated guinea-pig atrium (pD2 = 8.0) and H1-antagonistic activity (pA2 = 7.65) in the range of pheniramine. Analogues difluorinated in 3,4-(BU-E-75) or 3,5-position (BU-E-76) or chlorinated in 3,4-position (BU-E-64) are up to 160 times more potent H2-agonists than histamine. In contrast to other types of guanidines, in the arpromidine series the order of potency found in guinea-pig atria was in good agreement with the results from isolated perfused guinea-pig hearts. In particular, the two-fold halogenated arpromidine analogues proved to be more potent positive inotropic agents than impromidine with lower stimulating effects on heart rate and reduced arrhythmogenic properties.
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, FRG.
authors.forename: A
authors.initials: A
authors.lastname: Buschauer
authors.forename: G
authors.initials: G
authors.lastname: Baumann
mesh_terms: D000818:Animals; D016275:Atrial Function; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017446:Impromidine; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010632:Pheniramine / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D007093:Imidazoles; D011970:Receptors, Histamine H2; D010632:Pheniramine; C060591:arpromidine; D017446:Impromidine