title: Antiparkinson concentrations of pramipexole and PHNO occupy dopamine D2(high) and D3(high) receptors.
abstract: Because the high-affinity state of dopamine D2 receptors, D2(High), is the functional state of D2, and because the proportion of D2 receptors in the high-affinity state correlates with dopamine behavioral supersensitivity, the present study was designed to determine the affinities of antiparkinson dopamine agonists at the D2(High) site by means of competition with [3H]domperidone. In contrast to [125I]iodosulpride or [3H]spiperone, which are not sensitive to low concentrations of dopamine agonists, [3H]domperidone readily reveals dissociation constants (K(i)) for antiparkinson agonists at D2(High) and D3(High) receptors. The K(i) values for the human cloned D2(High) and D3(High) receptors, respectively, were 19 and 9 nM for pramipexole, 0.24 and 0.6 nM for +PHNO, 0.7 and 1.3 nM for bromocriptine, 0.5 and 2.6 nM for apomorphine, and 0.09 and 0.25 nM for (-)N-propylnorapomorphine. After correcting for the fraction of drug bound to plasma proteins, the known clinical concentrations in plasma or plasma water of these drugs, including pramipexole and +PHNO, are sufficient to occupy and activate the high-affinity state of D2, D2(High), in treating Parkinson's disease. The D3(High) receptors are less selectively occupied by +PHNO, bromocriptine, apomorphine, and -NPA.
authors.affiliation: Department of Pharmacology, Medical Sciences Building, Toronto, Ontario, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
authors.forename: Françoise
authors.initials: F
authors.lastname: Ko
authors.forename: Matthäus
authors.initials: M
authors.lastname: Willeit
authors.forename: Patrick
authors.initials: P
authors.lastname: McCormick
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D004294:Domperidone / Q000378:metabolism; D018491:Dopamine Agonists / Q000378:metabolism* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism* / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000077487:Pramipexole; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000187:drug effects* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology; D014316:Tritium
chemical_list: D052160:Benzothiazoles; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D014316:Tritium; C042631:naxagolide; D004294:Domperidone; D000077487:Pramipexole