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Vol. 301, Issue 3, 1179-1189, June 2002
Departments of Psychiatry, Pharmacology, Chemistry, and Medicinal
Chemistry, and the Neuroscience Center, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina (J.D.K., H.P.S.-C., E.G.A.,
M.M.L., C.P.L., G.S.O., B.L.B., R.B.M.); Departments of Anatomy and
Neurobiology, and Psychiatry, Washington University School of Medicine,
St. Louis, Missouri (K.L.O., R.D.T.); and Department of Medicinal
Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal
Sciences, Purdue University, West Lafayette, Indiana (D.E.N.)
D2-like dopamine receptors mediate functional changes via
activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform
of a D2-like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the
dopamine agonists dihydrexidine (DHX) and
N-n-propyl-DHX are "functionally
selective". The current study explores the underlying mechanism using transfected MN9D cells and D2-producing
anterior pituitary lactotrophs. Both dopamine and DHX inhibited
adenylate cyclase activity in a concentration-dependent manner in both
systems, effects blocked by D2, but not D1,
antagonists. In the MN9D cells, quinpirole and
R-(
)-N-propylnorapomorphine (NPA) also
inhibited the K+-stimulated release of
[3H]dopamine in a concentration-responsive,
antagonist-reversible manner. Conversely, neither DHX, nor its analogs,
inhibited K+-stimulated [3H]dopamine release,
although they antagonized the effects of quinpirole. S-(+)-NPA actually had the reverse functional
selectivity profile from DHX (i.e., it was a full agonist at
D2L receptors coupled to inhibition of dopamine release,
but a weak partial agonist at D2L receptor-mediated
inhibition of adenylate cyclase). In lactotrophs, DHX had little
intrinsic activity at D2 receptors coupled to G
protein-coupled inwardly rectifying potassium channels, and
actually antagonized the effects of dopamine at these D2
receptors. Together, these findings provide compelling evidence for
agonist-induced functional selectivity with the D2L
receptor. Although the underlying molecular mechanism is controversial
(e.g., "conformational induction" versus "drug-active state
selection"), such data are irreconcilable with the widely held view
that drugs have "intrinsic efficacy".
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