title: Antiparkinson therapeutic potencies correlate with their affinities at dopamine D2(High) receptors.
abstract: To determine whether antiparkinson dopamine agonists preferentially act on the high-affinity or the low-affinity states of dopamine D1 and D2 receptors, the agonist potencies were obtained by competition against [(3)H]SCH23390 for D1(High) and D1(Low), and against [(3)H]domperidone for D2(High) and D2(Low). N-propylnorapomorphine and cabergoline were the most potent at D2(High), with dissociation constants of 0.18 and 0.36 nM, respectively. Other agonists had D2(High)K(i) values of 0.52 nM for quinagolide, 0.6 nM for (+)PHNO, 0.9 for bromocriptine, 1.8 nM for apomorphine, 2.4 nM for pergolide, 3 nM for quinpirole, and 6.2 nM for lergotrile. There was a clear correlation between the K(i) values at D2(High) and their therapeutic concentrations in the plasma water, as derived from the known concentrations after correction for the fraction bound to the human plasma proteins. The data suggest that D2(High) is the primary and common target for the antiparkinson action of dopamine agonists. Bromocriptine, cabergoline, lergotrile, pergolide, and pramipexole had no affinity for D1(High), consistent with the clinical observations that the D2-selective bromocriptine and pramipexole elicit low levels of dyskinesia.
authors.affiliation: Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. philip.seeman@utoronto.ca
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001552:Benzazepines / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004294:Domperidone / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D010078:Oxazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D013223:Statistics as Topic; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D014316:Tritium; C042631:naxagolide; D004294:Domperidone; D001058:Apomorphine; D004298:Dopamine