Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other dopamine receptor agonists.
Pramipexole, an amino-benzathiazole [(S)-4,5,6,7-tetrahydro-N-6-propyl-2, 6-benzothiazolediamine dihydrochloride monohydrate] direct-acting dopamine receptor agonist effective in treating Parkinson's disease, bound selectively and with high affinity to dopamine D2-like receptors, with highest affinity at dopamine D3 receptors. Ergot dopamine receptor agonists (bromocriptine, lisuride, pergolide) bound to both dopamine and non-dopamine receptors. Although all agonists depressed dopamine neuron firing, only pramipexole and quinpirole completely silenced firing when administered in slowly-accumulating doses. High-dose pergolide, but not other ergots, completely suppressed firing when given by a prompt bolus i.v. injection, suggesting efficacy limitations may have involved receptor desensitization for pergolide, but not for bromocriptine and lisuride. We conclude that pramipexole differs from ergot dopamine receptor agonists currently used in the treatment of Parkinson's disease by virtue of its selectivity for dopamine receptors, its preferential affinity for the dopamine D3 receptor subtype, and its greater efficacy for stimulating dopamine receptors, as indicated in these electrophysiology assays.
CNS Research Pharmacia & Upjohn, Inc., Kalamazoo, MI 49001, USA.
M F
MF
Piercey
W E
WE
Hoffmann
M W
MW
Smith
D K
DK
Hyslop
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D001971:Bromocriptine / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D000077487:Pramipexole; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*
D000978:Antiparkinson Agents; D052160:Benzothiazoles; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D001971:Bromocriptine; D000077487:Pramipexole