PMID: 9536001May 16, 1998Paper

Agonist and inverse agonist activity at the dopamine D3 receptor measured by guanosine 5'--gamma-thio-triphosphate--35S- binding

The Journal of Pharmacology and Experimental Therapeutics
MalmbergN Mohell

Abstract

In this study, the ligand-receptor-G protein interactions of the dopamine D3 receptor expressed in Chinese hamster ovary cells were investigated using guanosine 5'-[gamma-thio]triphosphate-[35S] ([35S]GTPgammaS) and receptor binding experiments. Dopamine stimulated the [35S]GTPgammaS binding in a guanine nucleotide, magnesium and sodium-dependent manner. Dopamine and quinpirole produced maximal stimulation of the [35S]GTPgammaS binding whereas (+)-7-OH-DPAT and (-)-3-PPP were partial agonists. Interestingly, several compounds previously classified as D2 receptor antagonists behaved as inverse agonists at the D3 receptor, i.e., they inhibited the basal [35S]GTPgammaS binding in a dose dependent fashion. Haloperidol, (+)-UH-232, (+)-AJ-76 and raclopride were full inverse agonists but clozapine was a partial inverse agonist. Pertussis toxin treatment abolished the D3 receptor-mediated agonist as well as inverse agonist responses, indicating the involvement of Gi/Go proteins in both processes. According to the ternary complex model, agonists should bind with higher affinity to the G protein coupled receptor (RG) and thereby shift the equilibrium from free receptor (R) toward RG, which produces a biological response. However, an inv...Continue Reading

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