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Protean Agonism at the Dopamine D₂ Receptor: (S)-3-(3-Hydroxyphenyl)-N-propylpiperidine Is an Agonist for Activation of G_o1 but an Antagonist/Inverse Agonist for G_i1,G_i2, and G_i3

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (J.R.L., G.M.); and Screening & Compound Profiling, GlaxoSmithKline Research & Development, Harlow, Essex, United Kingdom (A.W., S.R., B.P.)

A range of ligands displayed agonism at the long isoform of the human dopamine D₂ receptor, whether using receptor-G protein fusions or membranes of cells in which pertussis toxin-resistant mutants of individual G_i-family G proteins could be expressed in an inducible fashion. Varying degrees of efficacy were observed for individual ligands as monitored by their capacity to load [³⁵S]GTPS onto each of G_i1,G_i2,G_i3, and G_o1. By contrast, (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine was a partial agonist when G_o1 was the target G protein but an antagonist/inverse agonist at G_i1,G_i2, and G_i3. In ligand binding assays, dopamine identified both high- and low-affinity states at each of the dopamine D₂ receptor-G protein fusion proteins, and the high-affinity state was eliminated by guanine nucleotide. (S)-(–)-3-(3-Hydroxyphenyl)-N-propylpiperidine bound to an apparent single state of the constructs in which the D₂ receptor was fused to G_i1,G_i2, or G_i3. However, it bound to distinct high- and low-affinity states of the D₂ receptor-G_o1 fusion, with the high-affinity state being eliminated by guanine nucleotide. Likewise, although dopamine identified guanine nucleotide-sensitive high-affinity states of the D₂ receptor when expression of pertussis toxin-resistant forms of each of G_i1, G_i2, G_i3, and G_o1 was induced, (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine identified a high-affinity site only in the presence of G_o1. p-Tyramine displayed a protean ligand profile similar to that of (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine but with lower potency. These results demonstrate (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine to be a protean agonist at the D₂ receptor and may explain in vivo actions of this ligand.

Address correspondence to: Dr. G. Milligan, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K. E-mail: g.milligan{at}bio.gla.ac.uk

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