Synthesis and pharmacology of combined histamine H1-/H2-receptor antagonists containing diphenhydramine and cyproheptadine derivatives

Article abstract of DOI:10.1002/ardp.19963290206

The classical histamine H₁-receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b-d, 10) were connected with a 2-guanidinothiazole containing structure (28) derived from the H₂-receptor antagonist tiotidine in order to obtain combined H₁/H₂-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H₁- and H₂-receptor antagonist activity at the isolated guinea-pig ileum (H₁) and the isolated guinea-pig right atrium (H₂), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H₁-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative (30-32, 34), however, cause a decrease of H₂-receptor antagonist potency compared to the diphenhydramines (29a-d, 33a-d). Using nitroethenediamine as the polar group is apparently more favourable to H₁- and H₂-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H₁-receptor antagonist moiety (29c, d) display the most potent H₁- and H₂-receptor antagonist effects. The presented concept is a very promising way to combine H₁- and H₂-receptor antagonist properties in one molecule.