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Vol. 301, Issue 3, 1166-1178, 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 (D.M.M., J.D.K., M.M.L.,
H.S.C., Q.D.W., S.R.J., R.G.B., D.K.H., R.M.W., C.P.L., R.B.M.);
Central Nervous Systems Research, Pharmacia & Upjohn, Inc., Kalamazoo,
Michigan (D.K.H., M.P.); and Department of Medicinal Chemistry and
Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, Indiana (D.E.N.)
Dihydrexidine (DHX), the first high-affinity D1 dopamine
receptor full agonist, is only 10-fold selective for D1
versus D2 receptors, having D2 affinity similar
to the prototypical agonist quinpirole. The D2 functional
properties of DHX and its more D2 selective analog
N-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 D2L and D2S
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.
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