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OtherNEUROPHARMACOLOGY

Agonist and Inverse Agonist Activity at the Dopamine D3 Receptor Measured by Guanosine 5′-[γ-Thio]Triphosphate-[35S] Binding

Åsa Malmberg, Åsa Mikaels and Nina Mohell
Journal of Pharmacology and Experimental Therapeutics April 1998, 285 (1) 119-126;
Åsa Malmberg
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Åsa Mikaels
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Nina Mohell
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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′-[γ-thio]triphosphate-[35S] ([35S]GTPγS) and receptor binding experiments. Dopamine stimulated the [35S]GTPγS binding in a guanine nucleotide, magnesium and sodium-dependent manner. Dopamine and quinpirole produced maximal stimulation of the [35S]GTPγS 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]GTPγS 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 D3receptor-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 inverse agonist should bind with higher affinity to R than to RG and thereby inhibit the basal activity of the cell. We found that the high affinity agonist binding site (RG) was abolished by pertussis toxin treatment of the cells. However, the inverse agonists bound with the same affinity to untreated and pertussis toxin treated D3 receptor membranes. Thus, we found no evidence for the hypothesis that inverse agonists would shift the equilibrium from RG toward R by binding with higher affinity to R than to RG.

Footnotes

  • Send reprint requests to: Dr. Åsa Malmberg, Department of Molecular Pharmacology, Preclinical R & D, Astra Arcus AB, S-151 85 Södertälje, Sweden.

  • Abbreviations:
    G protein
    guanine nucleotide-binding protein
    [35S]GTPγS
    guanosine 5′-[γ-thio]triphosphate -[35S]
    (−)-3-PPP
    (−)-(S)-3-(3-hydroxyphenyl)-N-propylpiperidine
    (+)-7-OH-DPAT
    (+)-(R)-7-hydroxy-2-(dipropylamino)tetralin
    (+)-UH-232
    (+)-(1S,2R)-5-methoxy-1-methyl-2-(dipropylamino)tetralin
    (+)-AJ-76
    (+)-(1S,2R)-5-methoxy-1-methyl-2-(propylamino)tetralin
    CHO
    Chinese hamster ovary
    • Received July 15, 1997.
    • Accepted December 22, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 1
1 Apr 1998
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OtherNEUROPHARMACOLOGY

Agonist and Inverse Agonist Activity at the Dopamine D3 Receptor Measured by Guanosine 5′-[γ-Thio]Triphosphate-[35S] Binding

Åsa Malmberg, Åsa Mikaels and Nina Mohell
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 119-126;

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OtherNEUROPHARMACOLOGY

Agonist and Inverse Agonist Activity at the Dopamine D3 Receptor Measured by Guanosine 5′-[γ-Thio]Triphosphate-[35S] Binding

Åsa Malmberg, Åsa Mikaels and Nina Mohell
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 119-126;
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