Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs

Jason D. Kilts, Hilary S. Connery, Elaine G. Arrington, Mechelle M. Lewis, Cindy P. Lawler, Gerry S. Oxford, Karen L. O'Malley, Richard D. Todd, Bonita L. Blake, David E. Nichols, Richard B. Mailman

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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".

Original languageEnglish (US)
Pages (from-to)1179-1189
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume301
Issue number3
DOIs
StatePublished - 2002
Externally publishedYes

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Lactotrophs
Dopamine Agonists
Dopamine
Adenylyl Cyclases
Quinpirole
Dopamine D2 Receptors
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Pharmaceutical Preparations
Potassium Channels
Calcium Channels
GTP-Binding Proteins
dihydrexidine
Protein Isoforms
Brain

ASJC Scopus subject areas

  • Pharmacology

Cite this

Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs. / Kilts, Jason D.; Connery, Hilary S.; Arrington, Elaine G.; Lewis, Mechelle M.; Lawler, Cindy P.; Oxford, Gerry S.; O'Malley, Karen L.; Todd, Richard D.; Blake, Bonita L.; Nichols, David E.; Mailman, Richard B.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 301, No. 3, 2002, p. 1179-1189.

Research output: Contribution to journalArticle

Kilts, JD, Connery, HS, Arrington, EG, Lewis, MM, Lawler, CP, Oxford, GS, O'Malley, KL, Todd, RD, Blake, BL, Nichols, DE & Mailman, RB 2002, 'Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs', Journal of Pharmacology and Experimental Therapeutics, vol. 301, no. 3, pp. 1179-1189. https://doi.org/10.1124/jpet.301.3.1179
Kilts, Jason D. ; Connery, Hilary S. ; Arrington, Elaine G. ; Lewis, Mechelle M. ; Lawler, Cindy P. ; Oxford, Gerry S. ; O'Malley, Karen L. ; Todd, Richard D. ; Blake, Bonita L. ; Nichols, David E. ; Mailman, Richard B. / Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs. In: Journal of Pharmacology and Experimental Therapeutics. 2002 ; Vol. 301, No. 3. pp. 1179-1189.
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