A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260.
L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-N'-(3-methylphenyl)urea), interacted in a stereoselective and competitive manner with guinea pig stomach gastrin and brain cholecystokinin (CCK) receptors. The affinity of L-365,260 for both gastrin (Ki = 1.9 nM) and brain CCK-B (Ki = 2.0 nM) receptors was greater than 2 orders of magnitude higher than its affinity for peripheral pancreatic CCK-A receptors or various other receptors. L-365,260 exhibited a similar high affinity for brain CCK-B receptors of rats, mice and man. A somewhat lower affinity for gastrin and brain CCK-B (IC50 = 20-40 nM) receptors was observed in dog tissues. In vivo, oral administration of L-365,260 antagonized gastrin-stimulated acid secretion in mice (ED50 = 0.03 mg/kg), rats (ED50 = 0.9 mg/kg) and guinea pigs (ED50 = 5.1 mg/kg). L-365,260 did not affect basal acid secretion and did not antagonize histamine- or carbachol-stimulated acid secretion in mice. L-365,260 represents a potentially powerful new tool for investigating gastrin and brain CCK-B receptors, and possibly their role in physiology and disease.
Lotti
V J
VJ
Department of Microbial Pharmacometrics, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Chang
R S
RS
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones; D001923:Brain Chemistry / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D004285:Dogs; D005088:Exocrine Glands / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005755:Gastrins / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D051379:Mice; D010418:Pentagastrin / Q000378:metabolism; D010671:Phenylurea Compounds; D011708:Pylorus / Q000502:physiology; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000187:drug effects*; D013045:Species Specificity; D013329:Structure-Activity Relationship
D001570:Benzodiazepinones; D005755:Gastrins; D007457:Iodine Radioisotopes; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C058121:L 365260; D006632:Histamine; D002217:Carbachol; D002766:Cholecystokinin; D010418:Pentagastrin