Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase

J Pharmacol Exp Ther. 2002 Jun;301(3):1166-78. doi: 10.1124/jpet.301.3.1166.


Dihydrexidine (DHX), the first high-affinity D(1) dopamine receptor full agonist, is only 10-fold selective for D(1) versus D(2) receptors, having D(2) affinity similar to the prototypical agonist quinpirole. The D(2) functional properties of DHX and its more D(2) selective analog N-n-propyl-dihydrexidine (PrDHX) were explored in rat brain and pituitary. DHX and PrDHX had binding characteristics to D(2) receptors in rat striatum typical of D(2) 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 D(2) 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 D(2) receptors in striatum (predominantly postsynaptic receptor sites) with equal affinity as D(2) 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(2S) receptors, 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / metabolism*
  • Animals
  • Binding, Competitive / drug effects
  • Biological Availability
  • Corpus Striatum / drug effects
  • Corpus Striatum / enzymology
  • Corpus Striatum / metabolism
  • Dopamine / metabolism
  • Dopamine Agonists / chemistry
  • Dopamine Agonists / pharmacokinetics
  • Dopamine Agonists / pharmacology*
  • Injections, Subcutaneous
  • Male
  • Phenanthridines / pharmacokinetics
  • Phenanthridines / pharmacology
  • Pituitary Gland / drug effects
  • Pituitary Gland / enzymology
  • Prolactin / blood
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Synaptic Membranes / enzymology*
  • Synaptic Membranes / metabolism
  • Synaptic Membranes / physiology


  • Dopamine Agonists
  • Phenanthridines
  • Receptors, Dopamine D2
  • 4-methyl-N-n-propyldihydrexidine
  • dihydrexidine
  • Prolactin
  • Adenylyl Cyclases
  • Dopamine