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 D2 receptor short isoform (CHO-D2s) and in a behavioral model for post-synaptic agonism in rats. In [3H]-spiperone competition binding studies, aplindore showed high affinity for dopamine D2 and D3 receptors and low affinity for the dopamine D4, serotonin (5-HT)1A, 5-HT2 receptors and the α1-adrenoceptor. The high potency partial agonist activity of aplindore was demonstrated in [35S]guanosine 5′-O-(3-thiotriphosphate) ([35S]GTPγS) 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-D2S receptor cells also stably expressing chimeric Gαq/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]GTPγS 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 D2 receptor antagonist raclopride. The dopamine D2 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.