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Functionally Selective Dopamine D2, D3 Receptor Partial Agonists

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journal contribution
posted on 12.06.2014, 00:00 by Dorothee Möller, Ralf C. Kling, Marika Skultety, Kristina Leuner, Harald Hübner, Peter Gmeiner
Dopamine D2 receptor-promoted activation of Gαo over Gαi may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo­[1,5-a]­pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar Ki values were determined for D2L, D2S, and D3 receptors. Measurement of [35S]­GTPγS incorporation at D2S coexpressed with G-protein subunits indicated significant bias for promotion of Gαo1 over Gαi2 coupling for several test compounds. Functionally selective D2S activation was most striking for the carbaldoxime 8b (Gαo1, pEC50 = 8.87, Emax = 65%; Gαi2, pEC50 = 6.63, Emax = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D2S receptors. Ligand efficacy and selectivity between D2S and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo­[1,5-a]­pyridine moiety.