Relative blood-brain barrier permeabilities of the cholecystokinin receptor antagonists devazepide and A-65186 in rats

The blood-brain barrier permeabilities of the type-A cholecystokinin recept or antagonists devazepide and A-65186 (N-alpha-3-quinolinoyl-D-Glu-N,N-dipe ntylamide) have been compared with those of the reference compounds iodoant ipyrine, which readily penetrates the blood-brain barrier, and mannitol, wh ich does not. Anaesthetized rats received a bolus injection into the left c arotid artery of [C-14]iodoantipyrine (0.25 mu Ci) combined with [H-3]manni tol, [H-3]devazepide or [H-3]A-65186 (1 mu Ci each). Rats were decapitated 12s after injection and the brains were removed. Four samples of left cereb rum (ca 100 mg each) were solubilized overnight and C-14 and H-3 activity w ere measured. The brain-uptake index for each test compound was determined as [(H-3/C-14 for sample)]/[(H-3/C-14 for injectate)] x 100, with a value o f 100 representing blood-brain barrier permeability equal to that for iodoa ntipyrine. The brain-uptake index (mean +/- s.e.m.) was 1.6 +/- 0.3 for [H- 3]mannitol (n = 5), 90.6 +/- 4.1 for [H-3]devazepide (n = 7, P < 0.001 comp ared with mannitol) and 3.5 +/- 0.7 for [H-3]A-65186 (n = 4, P > 0.05 compa red with mannitol, P < 0.001 compared with devazepide). Thus, devazepide re adily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmac ological tools for determining whether cholecystokinin is acting peripheral ly or at brain sites beyond the blood-brain barrier to produce satiety or a ny other function mediated by the type A cholecystokinin receptor.