A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260

Abstract

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 (K i = 1.9 nM) and brain CCK-B (K i = 2.0 nM) receptors was > 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 (IC 50 = 20–40 nM) receptors was observed in dog tissues. In vivo, oral administration of L-365,260 antagonized gastrin-stimulated acid secretion in mice (ED 50 = 0.03 mg/kg), rats (ED 50 = 0.9 mg/kg) and guinea pigs (ED 50 = 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.