title: Conformational requirements for histamine H2-receptor inhibitors: a structure-activity study of phenylene analogues related to cimetidine and tiotidine.
abstract: Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H2 receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene unit. These compounds were evaluated for antagonism of the dimaprit-stimulated chronotropic response in the guinea pig atrium and inhibition of histamine stimulated secretion of gastric acid in the dog. In both series, biological activity is markedly dependent on the m-phenylene regioisomers. Histamine H2-receptor activity is retained in both series; however, in the tiotidine series, gastric antisecretory activity is significantly improved. Regardless of the end group, N-cyanoguanidine 1,1-diamino-2-nitroethene or 3,4-diamino-1,2,5-thiadiazole 1-oxide, each 3 3-(2-guanidino-4-thiazolyl)phenyl analogue was ca. 8 and 90 times more potent intravenously than tiotidine and cimetidine, respectively. The electronic influences of the phenylene unit on biological activity were also evaluated. It was concluded that the geometric constraints imposed by the m-phenylene connecting element were more important than electronic factors in binding events at the histamine H2 receptor.
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis*; D001681:Biological Assay; D002927:Cimetidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004285:Dogs; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005750:Gastric Juice / Q000187:drug effects / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D009200:Myocardial Contraction / Q000187:drug effects; D011968:Receptors, Histamine / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D001555:Benzene Derivatives; D006146:Guanidines; D006635:Histamine H2 Antagonists; D007202:Indicators and Reagents; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2; D013844:Thiazoles; C100117:homofolic acid; D002927:Cimetidine; C037425:1',2',3',4',5',6'-hexahydrohomofolic acid; D005492:Folic Acid; C023990:tiotidine