Synthesis and Pharmacology of Combined Histamine H 1 ‐/H 2 ‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

The classical histamine H 1 ‐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 H 2 ‐receptor antagonist tiotidine in order to obtain combined H 1 ‐/H 2 ‐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 H 1 ‐ and H 2 ‐receptor antagonist activity at the isolated guinea‐pig ileum (H 1 ) and the isolated guinea‐pig right atrium (H 2 ), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H 1 ‐receptors. The tricyclic cyproheptadine and its 10,11‐dihydro derivative ( 30–32, 34 ), however, cause a decrease of H 2 ‐receptor antagonist potency compared to the diphenhydramines ( 29a—d, 33a—d ). Using nitroethenediamine as the polar group is apparently more favourable to H 1 ‐ and H 2 ‐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 H 1 ‐receptor antagonist moiety ( 29c, d ) display the most potent H 1 ‐ and H 2 ‐receptor antagonist effects. The presented concept is a very promising way to combine H 1 ‐ and H 2 ‐receptor antagonist properties in one molecule.