COMBINED HISTAMINE H-1 H-2 RECEPTOR ANTAGONISTS - PART-II - PHARMACOLOGICAL HYBRIDS WITH PHENIRAMINE-LIKE AND TIOTIDINE-LIKE SUBSTRUCTURES/

Hybrid molecules combining the crucial structural features of both phe niramine-type histamine H-1 receptor antagonists and guanidinothiazole -type H-2 receptor antagonists have been synthesized and tested for in vitro pharmacological activity at the isolated ileum and the spontane ously beating right atrium of the guinea-pig. In the title compounds t he basic side chain nitrogen of the H-1 antagonist and the so-called ' polar group' (cyanoguanidine, urea, or nitroethenediamine) of the H-2 antagonist moiety have been linked by a polymethylene spacer. The new substances displayed high affinities to both histamine receptor subtyp es and a dual type of antagonism (surmountable/insurmountable) charact erized by a shift of the concentration response curves to the right ac companied by a depression of the maximal response to the agonist if th e antagonist concentration was greater than or equal to 100 nM. Highes t combined histamine antagonist activities were found in the nitroethe nediamine series with pK(B) values ranging from 8.16 to 9.03 in the il eum (H-1) and 7.0-8.05 in the atrium (H-2) (C) 1998 Elsevier Science B .V.