The effect of lipophilic substituents on the H2-histaminergic activity of some close analogues of impromidine.
The cimetidine-like moiety of the potent H2-agonist impromidine (9a) and three closely related guanidines (10a, 11a, and 12a) which are modified in the imidazolylpropyl portion, has been replaced by 2-[(2-pyridyl)methylthio]ethyl, 2-(benzylthio)ethyl and 3,3-diphenylpropyl substituents. Guanidines 10-12 were obtained from acidic hydrolysis of corresponding N-benzoyl guanidines 7, 8, and 15, accessible by successive aminolysis of diphenyl N-benzoyl carbonimidate (2) according to known methods. Compared with leads 10a and 11a lipophilic substitution affords almost equipotent H2-agonists 10b-d and 11b-d, while substituents with increasing lipophilicity enhance both intrinsic activity and potency of the weak partial agonist 12a at guinea-pig atrial H2-receptors. Guanidines 10-12 are weak H1-antagonists on the isolated guinea-pig ileum.
Sellier
C
C
Institute of Pharmacy, Freie Universität Berlin, Germany.
Elz
S
S
Buschauer
A
A
Schunack
W
W
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D017446:Impromidine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects
D006635:Histamine H2 Antagonists; D017446:Impromidine