D2 Receptor Partial Agonists: Treatment of CNS Disorders of Dopamine Function

A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinsons disease (PD), and restless legs syndrome (RLS). In such disorders, transmission in discrete DA pathways may range from hypoactivation to hyperactivation of DA receptors, particularly those of the D2 subtype, providing the rationale for treatment approaches that activate or block D2 receptors, respectively. However, full agonists or pure D2 receptor antagonists may not be optimal therapeutic approaches for their respective disorders for a number of reasons, including an inability to restore the aberrant DA pathways to a normal level of basal tone. D2 receptor partial agonists (D2PAs) are proposed to stabilize activity in DA pathways by dampening excessive (and/or by restoring deficient) D2 receptor stimulation thereby shepherding DA neurons back to a desired level of basal activity. Stabilizing aberrant DA activity without disrupting nondysfunctional DA neurons may provide a potentially improved approach for treating DA disorders. The status of DA D2PAs and their potential application to schizophrenia, BD, PD, and RLS is reviewed. Preclinical and clinical evidence supports the idea that dysfunctions of D2 receptors contribute to these CNS disorders. Diseases in which both hyper- and hypofunction of DA pathways are present may be particularly promising, and challenging, targets for D2PAs. Furthermore, different DA disorders may respond optimally to D2PAs with differing levels of intrinsic activity, with “DA deficiency” diseases responding more effectively to higher intrinsic activity D2PAs than “DA hyperactivation” diseases. Overall, current evidence supports the conclusion that D2PAs have significant potential as improved CNS therapies relative to classic full agonists and antagonists at D2 receptors.