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 journalArticlepeer-review

75 Scopus citations


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
Pages (from-to)1179-1189
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 2002


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