Structure-activity relationship of histamine H2-receptor agonists

Abstract

Methylation of histamine at the imidazole nucleus leads to most selective agonists [1, 2]. 2-Methyl-histamine preferentially stimulates histamine Hcreceptors, whereas 5(4)-methyl-histamine is a selective HE-receptor stimulating agonist.In order to determine the effect of substitution at C-5(4) of the imidazole nucleus on the interaction with H t and H2-receptors, various aliphatic, alicyclic and aromatic substituents were introduced at this position.Since the side chain methylated N~-methyl-histamine is active at both histamine receptors [2], being particularly more potent than histamine in evoking the stimulation of gastric acid secretion in the dog [3,4] and in the cat [5], N ~-methylated derivates of the C-5(4) substituted histamines were also prepared.In an attempt to demonstrate the stereoselectivity of atrial H2-receptors 5-amino-4,5,6,7-tetrahydrobenzimidazole [6] (ATHB), a racemic compound in which the histamine side chain is fixed by integration into a ring system, was resoluted into its optical isomers which were then investigated on their H t-and H2-activity. MethodsOptically active dibenzoyl-tartaric acid was used for resolution of the racemic mixture. The absolute configuration was determined by optical-rotatory-dispersion measurements [7] of the optically active N-phthalimido-4,5,6,7-tetrahydrobenzimidazoles.All compounds were tested on isolated strips of guinea-pig ileum (Ha) [1,8] and on the isolated spontaneously beating guinea-pig right atrium (HE) [1]. ResultsThe intrinsic activities, pD2-values, the agonist activities relative to histamine and the activity ratios estimated at both types of receptors were reported.N~-Methyl-histamine is distinctly more potent than histamine in stimulating atrial HE-receptors.Among several active derivates the C-5(4) methyl and ethyl-analogues of histamine and of N~-methyl-histamine are selective H2-receptor agonists with full intrinsic activity. Among them the N~,5(4)-dimethyl-histamine proved to be active with the same degree of selectivity as the known H xagonist 5 (4)-methyl-histamine.Of the two optical isomers of ATHB the S(-)-enantiomer is apparently more active at atrial H2-receptors than its R(+)-antipode, both equally showing little activity at ileal H t-receptors. ConclusionsAs demonstrated by the results the active C-5(4) substituted histamines and N'~-methyl-histamines are to various extents selective H2-receptor agonists.