title: Relationship between receptor occupancy at 37 degrees C and the anticonvulsant effect of flunitrazepam in rats.
abstract: In this investigation an attempt was made to evaluate quantitatively the relationship between benzodiazepine receptor occupancy and the anticonvulsant effect of flunitrazepam in rats. A graded measure of anticonvulsant effect was obtained on the basis of an elevation of pentylenetetrazol (PTZ) threshold concentrations. The concentration-anticonvulsant effect relationship could be described by the Emax model with an EC50 in cerebrospinal fluid of 2.9 +/- 0.8 micrograms/liter and an Emax of 227 +/- 22 mg/liter PTZ (mean +/- SE). In vitro receptor occupancy was determined in a crude brain homogenate at 0 and 37 degrees C, which yielded KD values of 2.2 +/- 0.2 and 26 +/- 2 micrograms/liter, respectively. The results obtained in both experiments were combined by focusing on free flunitrazepam concentrations. This strategy resulted in a nonlinear relationship between receptor occupancy and anticonvulsant effect of flunitrazepam, with 90% of the maximum response achieved at a degree of receptor occupancy of approximately 50% at 37 degrees C.
authors.affiliation: Division of Pharmacology, University of Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Hollander-Jansen
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
authors.forename: M W
authors.initials: MW
authors.lastname: Langemeijer
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D002849:Chromatography, Gas; D005445:Flunitrazepam / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010433:Pentylenetetrazole; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013696:Temperature
chemical_list: D000927:Anticonvulsants; D011963:Receptors, GABA-A; D005445:Flunitrazepam; D010433:Pentylenetetrazole