Combined histamine H1/H2 receptor antagonists: part II. Pharmacological hybrids with pheniramine- and tiotidine-like substructures.
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)
Wolf
C
C
Institut für Pharmazie, Freie Universität Berlin, K onigin-Luise-Strasse 2+4, D-14195 Berlin, Germany.
Schulze
F R
FR
Buschauer
A
A
Schunack
W
W
D000818:Animals; D016275:Atrial Function; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D010632:Pheniramine / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D010632:Pheniramine; D002927:Cimetidine; C023990:tiotidine