Glutamate agonists for treating schizophrenia have affinity for dopamine D2High and D3 receptors.
Although the glutamate agonist LY 404,039 has been used to treat schizophrenia, its closest congener LY 379,268 has an affinity for both glutamate and dopamine (DA) D2(High) receptors. Considering that all antipsychotics act on dopamine receptors, and considering that another laboratory reported that LY 379,268 did not have any affinity for the D2(High) receptor, it was necessary to examine whether such glutamate agonists have an affinity for D2 and D3 dopamine receptors in vitro. The present data show that 50-200 nM LY 379,268 inhibited the binding of [(3)H]domperidone and [(3)H](+)PHNO to cloned dopamine D2 receptors consistently and reproducibly by 16% with dissociation constants of 2.1 and 2.5 nM at D2(High), respectively. In addition, LY 379,268 inhibited the binding of [(3)H]domperidone and [(3)H](+)PHNO to cloned dopamine D3 receptors with dissociation constants of 130 and 10 nM, respectively. LY 379,268 also inhibited the binding of [(3)H]domperidone to rat striata with a dissociation constant of 22 nM, predicting a clinical antipsychotic dose of 80-100 mg/day. LY 379,268 appears to act as an agonist at D2(High) and as an antagonist at D3, because guanine nucleotide eliminated the competition at D2(High) but had no effect on the competition at D3. The findings indicate that this type of glutamate agonist, LY 379,268, has a significant affinity for D2(High) and D3 receptors.
Seeman
Philip
P
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada. Philip.seeman@utoronto.ca
Guan
Hong-Chang
HC
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004294:Domperidone / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism; D010837:Vitamin K 1 / Q000031:analogs & derivatives / Q000378:metabolism
C510195:2-phytyl-1,4-naphthoquinone; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018492:Dopamine Antagonists; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D014316:Tritium; D004294:Domperidone; D010837:Vitamin K 1