The Effect of Lipophilic Substituents on the H 2 ‐Histaminergic Activity of Some Close Analogues of Impromidine

The cimetidine‐like moiety of the potent H 2 ‐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) and three closely related guanidines ( 10a, 11a , and 12a ) which are modified in the imidazolylpropyl portion, has been replaced by 2‐[(2‐pyridyl)methylthio]ethyl, 2‐(benzylthio)ethyl and 3,3‐diphenylpropyl substituents.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 H 2 ‐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 H 2 ‐receptors. Guanidines 10–12 are weak H 1 ‐antagonists on the isolated guinea‐pig ileum.