Protean Agonism at the Dopamine D2 Receptor: (S)-3-(3-Hydroxyphenyl)-N-propylpiperidine Is an Agonist for Activation of Go1 but an Antagonist/Inverse Agonist for Gi1,Gi2, and Gi3

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Abstract
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 Gαi-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]GTPγS onto each of Gαi1,Gαi2,Gαi3, and Gαo1. By contrast, (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine was a partial agonist when Gαo1 was the target G protein but an antagonist/inverse agonist at Gαi1,Gαi2, and Gαi3. 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 Gαi1,Gαi2, or Gαi3. However, it bound to distinct high- and low-affinity states of the D2 receptor-Gαo1 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 Gαi1, Gαi2, Gαi3, and Gαo1 was induced, (S)-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine identified a high-affinity site only in the presence of Gαo1. 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.

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