Wolf C, Schulze F R, Buschauer A, Schunack W
Institut für Pharmazie, Freie Universität Berlin, K onigin-Luise-Strasse 2+4, D-14195 Berlin, Germany.
Eur J Pharm Sci. 1998 Jul;6(3):187-96. doi: 10.1016/s0928-0987(97)10017-3.
Hybrid molecules combining the crucial structural features of both pheniramine-type histamine H1 receptor antagonists and guanidinothiazole-type H2 receptor antagonists have been synthesized and tested for in vitro pharmacological activity at the isolated ileum and the spontaneously beating right atrium of the guinea-pig. In the title compounds the basic side chain nitrogen of the H1 antagonist and the so-called 'polar group' (cyanoguanidine, urea, or nitroethenediamine) of the H2 antagonist moiety have been linked by a polymethylene spacer. The new substances displayed high affinities to both histamine receptor subtypes and a dual type of antagonism (surmountable/insurmountable) characterized by a shift of the concentration response curves to the right accompanied by a depression of the maximal response to the agonist if the antagonist concentration was >/=100 nM. Highest combined histamine antagonist activities were found in the nitroethenediamine series with pKB values ranging from 8.16 to 9.04 in the ileum (H1) and 7.0-8.08 in the atrium (H2)
