Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist

The pharmacology of aplindore (DAB-452) was characterized in CHO-K1 cells stably transfected with the human dopamine D-2 receptor short isoform (CHO-D-2s) and in a behavioral model for post-synaptic agonism in rats. In [H-3]-spiperone competition binding studies, aplindore showed high affinity for dopamine D-2 and D-3 receptors and low affinity for the dopamine D-4, serotonin (5-HT)(1A), 5-HT2 receptors and the alpha 1-adrenoceptor. The high potency partial agonist activity of aplindore was demonstrated in [S-35]guanosine 5'-O-(3-thiotriphosphate) ([S-35]GTP gamma S) binding, extracellular signal-regulated kinase (ERK)-phosphorylation and intracellular calcium flux assay using fluorometric plate reader ([Ca2+](i)- FLIPR) format. The [Ca2+](i)-FLIPR assay was conducted with CHO-D-2S receptor cells also stably expressing chimeric G(alpha q/o)-proteins. In all assay modalities, the potencies and intrinsic activities of aplindore were lower than dopamine and higher than aripiprazole. In contrast to the [35S] GTP gamma S binding and ERK-phosphorylation assays, the [Ca2+](i)-FLIPR assay was able to detect the low partial agonist activity of SDZ 208-912. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, aplindore induced contralateral turning, which was blocked by the dopamine D-2 receptor antagonist raclopride. The dopamine D-2 receptor selective partial agonist profile of aplindore suggests that it should be effective for the treatment of dopaminergic-based disorders, such as schizophrenia and Parkinson's disease. (c) 2006 Elsevier B.V. All rights reserved.