Parkinson's disease and D₁ dopamine receptors

This article reviews the role of the D₁-like dopamine receptors in Parkinson's disease (PD), an idea supported by the location of D₁ receptors in key aspects of basal ganglia circuitry. The initial disappointing results with available partial D₁ agonists have been replaced by optimism as newer full D₁ agonists have been shown to be the only class of drugs that can decrease parkinsonism in primates to a degree comparable to levodopa. Most of the available D₁ agonists, however, have been plagued by several problems, including poor bioavailability due, at least in part, to the necessity of a catechol function. Three other development issues that have hampered some members of this class are tolerance, hypotension and seizures, although some of the newer drugs entering early development may have escaped these problems. Finally, scientific advances have suggested that therapeutic profiles may be improved either by targeting only one of the two D₁-like receptors or by developing drugs that can activate selectively only some D₁-mediated functions. These examples suggest that it is highly likely that the immense therapeutic potential of D₁ agonists will be realized in PD and several other important CNS disorders before the end of the decade.