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Research ArticleNEUROPHARMACOLOGY

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2 Receptors Linked to Adenylate Cyclase

David M. Mottola, Jason D. Kilts, Mechelle M. Lewis, Hilary S. Connery, Q. David Walker, Sara R. Jones, Raymond G. Booth, Deborah K. Hyslop, Monford Piercey, R. Mark Wightman, Cindy P. Lawler, David E. Nichols and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 1166-1178; DOI: https://doi.org/10.1124/jpet.301.3.1166
David M. Mottola
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Jason D. Kilts
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Mechelle M. Lewis
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Hilary S. Connery
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Q. David Walker
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Sara R. Jones
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Raymond G. Booth
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Deborah K. Hyslop
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Monford Piercey
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R. Mark Wightman
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Cindy P. Lawler
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David E. Nichols
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Richard B. Mailman
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This article has a correction. Please see:

  • Correction to “Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2 Receptors Linked to Adenylate Cyclase” - July 01, 2002

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 D2L and D2Sreceptors, 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.

Footnotes

  • ↵1 Dr. Montford Piercey is deceased.

  • This work was supported by National Institutes of Health Grants MH-53356, MH-40537, and MH-42705, by Training Grants DA-07244 and ES-07126, and by Center Grants HD-01130 and MH-03327. Portions of this work have been presented in the following abstracts: Mottola DM, Cook LL, Jones SR, Booth RG, Nichols DE, and Mailman RB (1991) Dihydrexidine, a selective dopamine receptor agonist that may discriminate postsynaptic D2 receptors. Soc Neurosci Abstr17:818; and Kilts JD, Nichols DE, Mailman RB, and Lawler CP (1997) The functionally selective agonist dihydrexidine inhibits adenylate cyclase in rat striatum via the D2 dopamine receptor. Soc Neurosci Abstr23:1777.

  • Abbreviations:
    DHX
    dihydrexidine
    PrDHX
    N-n-propyldihydrexidine
    NPA
    N-propylnorapomorphine
    3-PPP
    3-(3-hydroxyphenyl)-N-n-propylpiperidine
    GppNHp
    guanylylimidodiphosphate
    HPLC
    high-performance liquid chromatography
    5-HTP
    5-hydroxytryptophan
    RIA
    radioimmunoassay
    DA
    dopamine
    DOPAC
    3,4-dihydroxyphenylacetic acid
    HVA
    high-voltage activated
    5-HIAA
    5-hydroxyindoleacetic acid
    HPLC-EC
    high-performance liquid chromatography with electrochemical detection
    SCH23390
    R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
    SKF38393
    2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
    LY171555
    quinpirole
    CY 208,243
    (−)-(6aR,12bR)4,6,6a,7,8,12a-hexahydro-7-methylindolo[4,3-a]phenanthridine
    U-86170
    (R)-5-(di[2,3–3H2]propylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one
    • Received August 24, 2001.
    • Accepted March 5, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleNEUROPHARMACOLOGY

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2 Receptors Linked to Adenylate Cyclase

David M. Mottola, Jason D. Kilts, Mechelle M. Lewis, Hilary S. Connery, Q. David Walker, Sara R. Jones, Raymond G. Booth, Deborah K. Hyslop, Monford Piercey, R. Mark Wightman, Cindy P. Lawler, David E. Nichols and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1166-1178; DOI: https://doi.org/10.1124/jpet.301.3.1166

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Research ArticleNEUROPHARMACOLOGY

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2 Receptors Linked to Adenylate Cyclase

David M. Mottola, Jason D. Kilts, Mechelle M. Lewis, Hilary S. Connery, Q. David Walker, Sara R. Jones, Raymond G. Booth, Deborah K. Hyslop, Monford Piercey, R. Mark Wightman, Cindy P. Lawler, David E. Nichols and Richard B. Mailman
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1166-1178; DOI: https://doi.org/10.1124/jpet.301.3.1166
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