title: Comparative pharmacological study of ropinirole (SKF-101468) and its metabolites in rats.
abstract: The dopamine receptor agonist ropinirole (SKF-101468) is used to treat Parkinson's disease. Ropinirole is metabolized by two routes to a series of different metabolites although the predominant pathway is species-dependent. It is unknown whether any of the metabolites contribute to its antiparkinsonian activity and whether D3 or D2 receptor agonist activity plays a preferential role. Therefore ropinirole and its primary metabolites, SKF-104557, SKF-97930 and SKF-96990, and the rat metabolite, SKF-89124 were tested in the 6-hydroxydopamine lesion model of Parkinson's disease. SKF-89124 and SKF-96990 were also assayed in radioligand binding and microphysiometer functional assays at cloned human dopamine D2 and D3. Ropinirole and SKF-89124 were equipotent in-vivo, and produced dose-related increases in circling at 0.05-0.8 mg kg(-1), s.c. (ropinirole) and 0.05-0.75 mg kg(-1), s.c. (SKF-89124). Neither SKF-96990 or SKF-97930, at doses up to 15 mg kg(-1), increased the circling rate. Some circling was observed with 15 mg kg(-1) SKF-104557 but the response was less than half that produced by ropinirole (0.8 mgkg(-1)). SKF-104557 was 150-fold less potent than ropinirole. SKF-89124 possessed-30-fold higher affinity for D3 over D2 receptors in radioligand binding studies, but was not selective in the functional microphysiometer assay. SKF-96990 was 10-fold selective for D3 over D2 receptors in the radioligand binding assay. Ropinirole and SKF-104557 are 20-fold selective for D3 over D2 receptors in radioligand binding assays whereas in microphysiometry, selectivity is 10-fold. SKF-97930 is inactive in radioligand binding and microphysiometer assays. Primary metabolites of ropinirole did not contribute significantly to its activity in this model of Parkinson's disease. The lack of dopamine D3/D2 receptor selectivity for ropinirole rules out the possibility of attributing the degree of either D2 or D3 receptor activity to the behavioural efficacy of ropinirole.
authors.affiliation: SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
authors.forename: C
authors.initials: C
authors.lastname: Reavill
authors.forename: I
authors.initials: I
authors.lastname: Boyfield
authors.forename: M
authors.initials: M
authors.lastname: Coldwell
authors.forename: P
authors.initials: P
authors.lastname: Nelson
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000502:physiology; D050637:Receptors, Dopamine D3
chemical_list: D000978:Antiparkinson Agents; C493593:DRD3 protein, human; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C046649:ropinirole