Synthesis and histamine H2 agonistic activity of arpromidine analogues: replacement of the pheniramine-like moiety by non-heterocyclic groups☆

Abstract Analogues of the potent histamine H 2 agonist arpromidine, characterized by non-heterocyclic groups (phenyl, cyclohexyl, alkyl) instead of the pheniramine-like portion, were prepared and tested for their H 2 agonistic and H 1 antagonistic activity in the isolated guinea pig right atrium and ileum, respectively. In the diphenylpropylguanidine series an increase in H 2 agonistic potency resulted from mono- or difluorination at one or both phenyl rings in the meta and/or para position (p D 2 ≤ 7.75 vs p D 2 = 7.15 for the unsubstituted parent compound). Compounds chlorinated at both phenyl rings were considerably less potent. Highest combined H 2 agonistic/H 1 antagonistic potency was found in the 4-fluorophenyl series. The arpromidine analogue with cyclohexyl and methyl group instead of phenyl and pyridine ring proved to be 30 times more potent than histamine in the atrium. The H 1 antagonistic potency in cyclohexyl compounds was lower than in the diaryl series. Thus, aromatic rings appear not to be required for high H 2 agonistic potency but are useful for combined H 2 agonistic/H 1 antagonistic activity.