title: AHR-9294: a novel inhibitor of H,K-ATPase antagonizes gastric HCl secretion in vivo.
abstract: 8-Methoxy-4-[(2-isopropylphenyl)amino]-3-quinolinecarboxylate ethyl ester (AHR-9294) inhibited acid secretion stimulated by histamine, pentagastrin or carbachol in rats, and by histamine or feeding in dogs. AHR-9294 was about half as potent as omeprazole and exhibited a shorter duration of action. Based on its inhibition of acid secretion induced by different secretagogues and its lack of effect on histamine-stimulated adenylate cyclase activity, AHR-9294 does not appear to operate at the histamine receptor or adenylate cyclase. Rather, studies on enriched oxyntic microsomal preparations showed AHR-9294 to be an effective inhibitor of the H+ pump enzyme, H,K-ATPase, suggesting this might be the site of antisecretory activity. Kinetic studies revealed that inhibition of both K(+)-activated ATPase and p-nitrophenylphosphatase by AHR-9294 was purely competitive with K+ and its congeners, indicating that AHR-9294 and its analogs belong to the class of compounds known as "K+)-site" inhibitors. On the other hand, inhibition by AHR-9294 was noncompetitive with both ATP and p-nitrophenylphosphatase on their respective rates of hydrolysis (i.e., both Vmax and the apparent Km were reduced, but Vmax/Km was unchanged). Studies on partial reactions of the H,K-ATPase showed that the rate of ATP/ADP exchange was unaffected by AHR-9294 and the steady-state level of phosphoenzyme was only partially reduced (thus ATP/enzyme interaction was not affected); however, the rate of K(+)-catalyzed dephosphorylation of phosphoenzyme was markedly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley.
authors.forename: W W
authors.initials: WW
authors.lastname: Reenstra
authors.forename: L M
authors.initials: LM
authors.lastname: Pinkus
authors.forename: J
authors.initials: J
authors.lastname: Bailey
authors.forename: W L
authors.initials: WL
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Droppleman
authors.forename: L F
authors.initials: LF
authors.lastname: Sancilio
authors.forename: J G
authors.initials: JG
authors.lastname: Forte
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase; D006633:Histamine Antagonists / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010418:Pentagastrin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine
chemical_list: D000897:Anti-Ulcer Agents; D006633:Histamine Antagonists; D011804:Quinolines; C074340:AHR 9294; D002217:Carbachol; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D010418:Pentagastrin; D009853:Omeprazole