The Effect of Lipophilic Substituents on the H₂‐Histaminergic Activity of Some Close Analogues of Impromidine

Abstract

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(9a) and three closely related guanidines (10a, 11a, and 12a) which are modified in the imidazolylpropyl portion, has been replaced by 2-[(2-pyridyl)methylthio]ethyl, 2-(benzylthio)ethyl and 3,3-diphenylpropyl substituents.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.

Structure-Activity Relationships of Histamine H2 Receptor Ligands+

“…The structural analogues of impromidine described in the literature include, for example, chiral compounds with branched cimetidine-like or homohistamine partial structures [44,45] or substances characterised by other substructures from H 2 R antagonists like thiazoles and furans derived from tiotidine, nizatidine and ranitidine [46,47]. Completely different structures replacing the 5-methylimidazole group are present in the case of hybrid molecules combining the imidazolylpropylguanidine moiety with, for example, arylalkyl [48][49][50][51][52][53][54][55][56], diarylalkyl originating from H 1 R antagonists [57][58][59][60][61], dihydropyridine from calcium channel blockers [62,63] and benzoylimidazolone groups [64] from phosphodiesterase inhibitors (for reviews see [15,65,66]). Examples of H 2 R-selective guanidine-type agonists are depicted in (Fig.…”