title: Dopamine D(2) activity of R-(-)-apomorphine and selected analogs: a microdialysis study.
abstract: In the present study, R-(-)-apomorphine and three of its analogs were studied for their potency in decreasing the release of dopamine in the striatum after subcutaneous administration and for their oral bioavailability using the microdialysis technique in freely moving rats. The analogs R-(-)-N-n-propylnorapomorphine and R-(-)-11-hydroxy-N-n-propylnoraporphine displayed a higher potency than R-(-)-apomorphine in decreasing the release of dopamine in the striatum. A high dose of R-(-)-11-hydroxyaporphine, a dopamine D(2) receptor partial agonist, had a small effect on the release of dopamine in the striatum. The catechols R-(-)-N-n-propylnorapomorphine and R-(-)-apomorphine displayed a comparable oral bioavailability (1%), while the mono-hydroxy analog R-(-)-11-hydroxy-N-n-propylnoraporphine displayed a slightly higher oral bioavailability (3%). In conclusion, R-(-)-N-n-propylnorapomorphine and R-(-)-11-hydroxy-N-n-propylnoraporphine did not show a substantial improvement in bioavailability. However, due to the clear difference in their efficacy in decreasing dopamine release, in spite of the similar agonist binding affinities to the dopamine D(2) receptor of the two analogs compared to R-(-)-apomorphine, they could be useful alternatives for apomorphine in the treatment of Parkinson's disease.
authors.affiliation: Department of Medicinal Chemistry, University Center of Pharmacy, University of Groningen, A. Deusinglaan 1, NL-9713 AV, Groningen, Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Rodenhuis
authors.forename: D
authors.initials: D
authors.lastname: Dijkstra
authors.forename: P
authors.initials: P
authors.lastname: de Boer
authors.forename: E S
authors.initials: ES
authors.lastname: Vermeulen
authors.forename: W
authors.initials: W
authors.lastname: Timmerman
authors.forename: H V
authors.initials: HV
authors.lastname: Wikström
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D001058:Apomorphine; D004298:Dopamine