Binding of antipsychotic drugs at α_1A- and α_1B-adrenoceptors: risperidone is selective for the α_1B-adrenoceptors

The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the α₁-adrenoceptor. Saturation experiments showed that [³H]prazosin labelled a single population of binding sites in the spleen (α_{1A and α1B}) (dissociation constants (K_D): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the α_1A-adrenoceptor. Furthermore, the affinities for the α_1A- and α_1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the α₁-adrenoceptor subtypes. Risperidone was 120-fold more selective for the α_1B-adrenoceptor with respect to the α_1A-adrenoceptor (K_i values: 2.3 ± 1.2 nM and 283.6±174.1 nM respectively).