D2 receptor partial agonists: treatment of CNS disorders of dopamine function

Abstract

A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinson's 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 D(2) subtype, providing the rationale for treatment approaches that activate or block D(2) receptors, respectively. However, full agonists or pure D(2) 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. D(2) receptor partial agonists (D(2)PAs) are proposed to stabilize activity in DA pathways by dampening excessive (and/or by restoring deficient) D(2) receptor stimulation thereby shepherding DA neurons back to a desired level of basal activity. Stabilizing aberrant DA activity without disrupting non-dysfunctional DA neurons may provide a potentially improved approach for treating DA disorders. The status of DA D(2)PAs and their potential application to schizophrenia, BD, PD, and RLS is reviewed. Preclinical and clinical evidence supports the idea that dysfunctions of D(2) 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 D(2)PAs. Furthermore, different DA disorders may respond optimally to D(2)PAs with differing levels of intrinsic activity, with "DA deficiency" diseases responding more effectively to higher intrinsic activity D(2)PAs than "DA hyperactivation" diseases. Overall, current evidence supports the conclusion that D(2)PAs have significant potential as improved CNS therapies relative to classic full agonists and antagonists at D(2) receptors.