Pharmacological evidence for selective inhibition of gastric acid secretion by telenzepine, a new antimuscarinic drug.
The new antisecretory drug, telenzepine (4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl)acetyl]-10H-thieno-[3,4 - b][1,5]benzodiazepin-10-one), was investigated for its inhibition of functionally intact muscarinic receptors involved in gastric acid secretion in rabbit fundic glands, perfused mouse stomach in vitro, perfused rat stomach in situ, gastric fistula in rats and dogs with a Heidenhain pouch. The effects on these receptors were contrasted with effects on receptors located on smooth muscle and heart, i.e. isolated rat urinary bladder, stomach and atrium. The results were compared to those values obtained with nonselective antimuscarinic drugs (N-methylscopolamine, atropine) and the selective M-1 antagonist pirenzepine. Telenzepine was found to be 4-10 times more potent than pirenzepine with respect to depressing both gastric acid secretion and smooth muscle or myocardial responses. Based on -log EC50 and pA2 values, both drugs exhibited a similar selectivity profile differing from the pattern of effects observed with atropine or a second reference compound, zolenzepine. As compared with atropine, telenzepine exhibited a 5 fold higher relative affinity to muscarinic receptors involved in gastric acid secretion. It was concluded that telenzepine is selective to discriminate between muscarinic receptors mediating gastric acid secretion and affecting muscle contractility and that this finding supports the concept of muscarinic receptor heterogeneity.
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D010890:Pirenzepine / Q000031:analogs & derivatives*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects; D013270:Stomach / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects
D001570:Benzodiazepinones; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D000632:Aminopyrine; C046338:telenzepine; D010890:Pirenzepine