title: "Full" dopamine D1 agonists in human caudate: biochemical properties and therapeutic implications.
abstract: Recent data indicate that full D1 dopamine agonists have greater antiparkinsonian effects in the MPTP primate model than do partial agonists, suggesting that the intrinsic activity of D1 agonists may affect their utility in the treatment of Parkinson's disease. It is unclear, however, whether human D1 receptors in situ are similar to D1 receptors in other species or in molecular expression systems. For this reason, the binding affinity and functional activity of a series of D1 dopamine receptor agonists [dihydrexidine (DHX), SKF82958, and A68930] were determined in postmortem human caudate. Results from in vitro binding studies with membranes from human caudate indicate that these D1 agonists competed for [3H]SCH23390 labeled sites with a rank order similar to that found in rat striatum [K50 = 36.8 nM (DHX); 18.6 nM (SKF82958); 3.9 nM (A68930)]. The ability of these compounds and the partial agonist SKF38393 to stimulate the enzyme adenylyl cyclase in tissue homogenates of human caudate was also examined. DHX and A68930 are full agonists compared to dopamine, whereas SKF82958 and SKF38393 are partial agonists. These differences in biochemical intrinsic activity are consistent with the profound antiparkinsonian effects caused by DHX, but not by SKF82958 and SKF38393, in the MPTP-monkey model. This suggests that DHX and A68930 may be of greater utility in treating disorders where a full efficacy D1 agonist may be required.
authors.affiliation: Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill 27599-7160, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Gilmore
authors.forename: V J
authors.initials: VJ
authors.lastname: Watts
authors.forename: C P
authors.initials: CP
authors.lastname: Lawler
authors.forename: E P
authors.initials: EP
authors.lastname: Noll
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
authors.forename: R B
authors.initials: RB
authors.lastname: Mailman
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects; D001344:Autopsy; D001552:Benzazepines / Q000494:pharmacology; D001667:Binding, Competitive; D002421:Caudate Nucleus / Q000187:drug effects*; D004298:Dopamine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010300:Parkinson Disease; D017447:Receptors, Dopamine D1 / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; C071262:SK&F 82958; D000262:Adenylyl Cyclases; D004298:Dopamine