title: Measurement of central nervous system activity of systemically administered CCKB receptor antagonists by ex vivo binding.
abstract: In the present study we have described an ex vivo binding assay in mice to measure the central nervous system (CNS) activity of systemically administered CCKB receptor antagonists. This assay incorporated a transcardiac perfusion step to remove the residual blood from the brain, which otherwise may result in an overestimation of CNS activity. The benzodiazepine CCKB receptor antagonist L-365,260 had marked CNS activity in this assay following i.v. (ED50 12.0 mg/kg) and p.o. (ED50 20.0 mg/kg) administration, whereas the dipeptoid CCKB receptor antagonist, CI988 exhibited relatively weak CNS activity following i.v. injection (ED50 > 30.0 mg/kg). In contrast, following i.c.v. administration, CI988 potently inhibited ex vivo binding of [125I]Bolton Hunter-CCK-8S to mouse brain. The recently described acidic tetrazole CCKB receptor antagonist, L-368,935 had potent CNS activity with an ED50 of 5.6 mg/kg i.v. and an ED50 of 1.9 micrograms/kg i.c.v. These studies suggest that the weak CNS activity of CI988 following systemic injection may, in part, be due to poor brain penetration and that the ex vivo binding assay is a useful way of assessing the brain penetration of CCKB receptor antagonists.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: K L
authors.initials: KL
authors.lastname: Chapman
authors.forename: A
authors.initials: A
authors.lastname: Heald
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D008536:Meglumine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D010671:Phenylurea Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000031:analogs & derivatives / Q000378:metabolism; D013388:Succinimides / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001570:Benzodiazepinones; C044758:Bolton Hunter-cholecystokinin octapeptide; D007211:Indoles; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D013388:Succinimides; D013777:Tetrazoles; D001569:Benzodiazepines; C065599:PD 134308; C087236:L 368935; C058121:L 365260; D008536:Meglumine; D012844:Sincalide