Binding of a radiolabeled triazolopyridazine to a subtype of benzodiazepine receptor in the rat cerebellum.
The triazolopyridazine (TPZ) drugs, typified by CL218,872 (CL), have a relatively higher affinity for a subpopulation of benzodiazepine (BZ) receptors. The binding of radiolabeled CL to membranes from rat cerebellum, a region enriched in the TPZ-preferring ("Type 1") BZ receptor, was characterized and compared with that of [3H]flunitrazepam ([3H]FLU) in the same preparation. [3H]CL had clonazepam displaceable binding which was saturable. The Kd was approximately 21 nM and the Bmax was approximately 600 fmol/mg of protein. [3H]CL binding was similar to that for [3H]FLU in that exogenous gamma-aminobutyric acid (GABA) enhanced the binding; however, [3H]CL binding differed from that for [3H]FLU in that anions, cartazolate and pentobarbital did not enhance [3H]CL binding. These data suggest that [3H]CL binds to the Type 1 BZ receptor in a manner different from that of a BZ drug such as FLU. Inasmuch as GABA enhances [3H]CL binding, but anions, cartazolate and pentobarbital do not, [3H]CL may bind to the Type 1 BZ receptor in such a way that it interacts with the GABA site, but perhaps not directly with the ionophore or the postulated pyrazolopyridine-barbiturate site. Thus, TPZ drugs may affect the GABA receptor complex in a different or perhaps less extensive way than the BZs. This, in addition to the regional localization of the Type 1 receptor, may be an important part of the mechanism of action of the TPZs.
D000818:Animals; D000838:Anions / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D005445:Flunitrazepam / Q000378:metabolism; D008297:Male; D010424:Pentobarbital / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D011724:Pyridazines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011955:Receptors, Drug / Q000378:metabolism*; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000838:Anions; D011720:Pyrazoles; D011724:Pyridazines; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C021604:CL 218872; C006315:cartazolate; D010424:Pentobarbital