Selective anxiolytics: are the actions related to partial "agonist" activity or a preferential affinity for...

Both pharmacological and biochemical evidence support the existence of BZ receptor subtypes. Determination of the molecular basis of BZ receptor heterogeneity requires additional research. The physiological significance of BZ receptor subtypes is not currently understood. One hypothesis presented to explain the unique pharmacological effects of CL 218872 suggests that CL 218872 has preferential affinity for a BZ receptor subtype (i.e., type I sites) that mediates the anxiolytic effects of the clinically active BZs. An alternative hypothesis has been proposed to account for these observations and is based upon the possibility that CL 218872 may act as a partial agonist at the BZ receptor. The partial agonist theory is supported by behavioral evidence and the relatively small differences in affinity of the BZ receptor subtypes discriminated by CL 218872 at physiological temperatures. In addition, in vivo binding studies suggest that occupancy of type II BZ receptor subtypes (i.e., those with low affinity for CL 218872) is necessary for CL 218872 to produce minimal anticonflict activity (4). Unlike certain other neurotransmitter systems, it is difficult to correlate the heterogeneous binding properties of BZ receptor ligands with their agonist/antagonist potential at BZ receptor. For example, CL 218872 discriminates BZ receptor subtypes and acts as an agonist at the BZ receptor. Beta-carbolines such as PCC also discriminate receptor subtypes, yet they act as antagonists at the BZ receptor. Compounding the complexity, neither the nature nor the existence of an endogenous ligand is known. So, the designation of agonist or antagonist effects is made on a purely functional basis.(ABSTRACT TRUNCATED AT 250 WORDS)