title: Dinapsoline: characterization of a D1 dopamine receptor agonist in a rat model of Parkinson's disease.
abstract: Dinapsoline is a new potent, full agonist at D1 dopamine receptors with limited selectivity relative to D2 receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of Parkinson's disease. Dinapsoline produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D1 receptor antagonist SCH-23390, but not by the D2 receptor antagonist raclopride. During a chronic 14-day treatment period in which rats received dinapsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D1:D2 selectivity in vitro than other D1 agonists, the contribution of D2 activity to tolerance was assessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In contrast, when dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D1 and D2 receptors to tolerance, experiments were performed with the selective D1 agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D2 agonist quinpirole plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D1 receptor agonists is influenced by the pattern of drug exposure but not by the D1:D2 selectivity of the agonist.
authors.affiliation: Neuroscience/Genitourinary Drug Discovery, Bristol-Myers Squibb Inc., Wallingford, Connecticut 06492, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Gulwadi
authors.forename: C D
authors.initials: CD
authors.lastname: Korpinen
authors.forename: R B
authors.initials: RB
authors.lastname: Mailman
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
authors.forename: S Y
authors.initials: SY
authors.lastname: Sit
authors.forename: M T
authors.initials: MT
authors.lastname: Taber
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006892:Hydroxydopamines; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D009284:Naphthols / Q000627:therapeutic use*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy*; D019257:Quinpirole / Q000627:therapeutic use; D020891:Raclopride / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects; D013563:Sympathectomy, Chemical
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D006892:Hydroxydopamines; D007546:Isoquinolines; D009284:Naphthols; D017447:Receptors, Dopamine D1; C097827:dinapsoline; D019257:Quinpirole; D020891:Raclopride; D004298:Dopamine