Relationship between inhibition of cyclic AMP production in Chinese hamster ovary cells expressing the rat D2(444) receptor and antagonist/agonist binding ratios.
1. Radioligand binding assays using [3H]-(-)-sulpiride, in the presence of 1 mM ethylenediaminetetraacetic acid (EDTA) and 100 microM guanylylimidodiphosphate (GppNHp) and [3H]-N0437 were developed to label the low and high agonist affinity states of the rD2(444) receptor (long form of the rat D2 receptor) respectively. The ratios of the affinities of compounds in these two assays (Kapp [3H]-(-)-supiride/Kapp [3H]-N-0437) were then calculated. 2. The prediction that the binding ratio reflected the functional efficacy of a compound was supported by measurement of the ability of a number of compounds acting at dopamine receptors to inhibit rD2(444)-mediated inhibition of cyclic AMP production. When the rank order of the ratios of a number of these compounds was compared to their ability to inhibit the production of cyclic AMP, a significant correlation was seen (Spearman rank correlation coefficient = 0.943, P = 0.01). 3. In conclusion, the sulpiride/N-0437 binding ratio reliably predicted the efficacy of compounds acting at dopamine receptors to inhibit cyclic AMP production mediated by the rD2(444) receptor.
Harley
E A
EA
Merck Sharp Laboratory Terlings Park, Harlow, Essex.
Middlemiss
D N
DN
Ragan
C I
CI
D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018491:Dopamine Agonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013469:Sulpiride / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism; D013876:Thiophenes / Q000378:metabolism; D014162:Transfection
D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D013469:Sulpiride; C047508:rotigotine; D000242:Cyclic AMP