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 receptor antagonists devazepide and A-65186 (N(α)-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not. Anaesthetized rats received a bolus injection into the left carotid artery of [¹⁴C]iodoantipyrine (0.25 μCi) combined with [³H]mannitol, [³H]devazepide or [³H]A-65186 (1 μCi each). Rats were decapitated 12 s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and ¹⁴C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(³H/¹⁴C for sample)]/[(³H/¹⁴C for injectate)] x 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean ± s.e.m.) was 1.6 ± 0.3 for [³H]mannitol (n = 5), 90.6 ± 4.1 for [³H]devazepide (n = 7, P <0.001 compared with mannitol) and 3.5 ± 0.7 for [³H]A-65186 (n = 4, P > 0.05 compared with mannitol, P <0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood-brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.