TY - JOUR
T1 - Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs
AU - Kilts, Jason D.
AU - Connery, Hilary S.
AU - Arrington, Elaine G.
AU - Lewis, Mechelle M.
AU - Lawler, Cindy P.
AU - Oxford, Gerry S.
AU - O'Malley, Karen L.
AU - Todd, Richard D.
AU - Blake, Bonita L.
AU - Nichols, David E.
AU - Mailman, Richard B.
PY - 2002
Y1 - 2002
N2 - 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".
AB - 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".
UR - http://www.scopus.com/inward/record.url?scp=0036267278&partnerID=8YFLogxK
U2 - 10.1124/jpet.301.3.1179
DO - 10.1124/jpet.301.3.1179
M3 - Article
C2 - 12023553
AN - SCOPUS:0036267278
SN - 0022-3565
VL - 301
SP - 1179
EP - 1189
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -