Abstract

Dihydrexidine (DHX), the first high-affinity D₁ dopamine receptor full agonist, is only 10-fold selective for D₁versus D₂ receptors, having D₂ affinity similar to the prototypical agonist quinpirole. The D₂ functional properties of DHX and its more D₂ selective analogN-n-propyl-dihydrexidine (PrDHX) were explored in rat brain and pituitary. DHX and PrDHX had binding characteristics to D₂ receptors in rat striatum typical of D₂ agonists, binding to both high- and low-affinity sites and being sensitive to guanine-nucleotides. Consistent with these binding data, both DHX and PrDHX inhibited forskolin-stimulated cAMP synthesis in striatum with a potency and intrinsic activity equivalent to that of quinpirole. Unexpectedly, however, DHX and PrDHX had little functional effect at D₂ receptors expressed on dopaminergic neurons that mediate inhibition of cell firing, dopamine release, or dopamine synthesis. Quantitative receptor competition autoradiography demonstrated that DHX bound to D₂ receptors in striatum (predominantly postsynaptic receptor sites) with equal affinity as D₂ sites in the substantia nigra (autoreceptor sites). The data from these experiments, coupled with what is known about the location of specific dopamine receptor isoforms, lead to the hypothesis that DHX, after binding to D_2L and D_2Sreceptors, causes agonist-typical functional changes only at some of these receptors. This phenomenon (herein termed “functional selectivity”) suggests that drugs may be targeted not only at specific receptor isoforms but also at separate functions mediated by a single isoform, yielding novel approaches to drug discovery.