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Publication Detail

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

Authors: 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

Published In J Pharmacol Exp Ther, (2002 Jun)

Abstract: D(2)-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 D(2)-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 D(2)-producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentration-dependent manner in both systems, effects blocked by D(2), but not D(1), antagonists. In the MN9D cells, quinpirole and R-(-)-N-propylnorapomorphine (NPA) also inhibited the K(+)-stimulated release of [(3)H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K(+)-stimulated [(3)H]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 D(2L) receptors coupled to inhibition of dopamine release, but a weak partial agonist at D(2L) receptor-mediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D(2) receptors coupled to G protein-coupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D(2) receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D(2L) 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".

PubMed ID: 12023553 Exiting the NIEHS site

MeSH Terms: Animals; Cell Line; Dopamine Agonists/pharmacology*; Dopamine/physiology; Dose-Response Relationship, Drug; Female; Membrane Potentials/drug effects; Membrane Potentials/physiology; Phenanthridines/pharmacology*; Pituitary Gland, Anterior/cytology; Pituitary Gland, Anterior/drug effects*; Pituitary Gland, Anterior/metabolism; Potassium Channels/metabolism; Prolactin/metabolism; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2/agonists*; Receptors, Dopamine D2/physiology; Transfection*/methods; Transfection*/statistics & numerical data

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