Structural modification of H2-receptor antagonists provide post-H2-receptor gastric antisecretory activity.
Structural analogues (e.g., Wy-46,499) of a known H2-antagonist (Wy-45,662) were found to inhibit acid secretion in the pylorus ligated rat and to block forskolin and DBcAMP-stimulated [14C]amino-pyrine (AP) uptake by rat isolated gastric mucosal cell preparations. Wy-45,662 (N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno [3,4- d]isothiazol-3-amine 1, 1-dioxide), a very potent histamine H2-antagonist and antisecretory agent in the rat (ED50 approximately equal to 0.3 mg/kg), had no effect in vitro at 1 microM on forskolin-induced [14C]AP uptake while 10 nM Wy-45,662 completely suppressed histamine-stimulated [14C]AP uptake. In contrast, the N-benzylated form of Wy-45,662, Wy-46,499, dose-dependently (1 X 10(-7) -3 X 10(-6)M) suppressed forskolin-stimulated [14C]AP uptake while retaining modest antisecretory activity (ED50 approximately equal to 8 mg/kg) in vivo. Wy-46,499's modest antisecretory activity was thus attributable to inhibition via a post-histamine H2-receptor mechanism.
D000818:Animals; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D050198:Phenoxypropanolamines; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
D006635:Histamine H2 Antagonists; D050198:Phenoxypropanolamines; D013844:Thiazoles; C054257:Wy 46499; C051466:Wy 45662