CL 218,872 Binding to Benzodiazepine Receptors in Rat Spinal Cord: Modulation by ?-Aminobutyric Acid and Evidence for Receptor Heterogeneity

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Abstract
The binding of the triazolopyridazine CL 218,872 to central benzodiazepine receptors identified with [3H]Ro 15-1788 [ethyl-8-flouro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol-1,5a-1,4-benzodiazepine-3-carboxylate] was studied in extensively washed homogenates of rat spinal cord and cerebral cortex. CL 218,872 displacement curves were shallow in both spinal cord (nH = 0.67) [Hill coefficient] and cortex (nH = 0.54), suggesting the presence of type 1 and type 2 benzodiazepine receptors in both tissues. CL 218,872 had lower affinity in spinal cord (IC50 = 825 nM) [median inhibitory concentration dosage] than cortex (IC50 = 152 nM), possibly reflecting the presence of fewer type 1 sites in the cord. Activating GABA receptors with 10 .mu.M muscimol resulted in a 2- to 3-fold increase in CL 218,872 affinity in both tissues without changes in the displacement curve slope. Evidently, GABA enhances CL 218,872 affinity for both type 1 and type 2 sites in both spinal cord and cerebral cortex.