Abstract
Dopamine D2 receptor-promoted activation of Gα(o) over Gα(i) 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 K(i) values were determined for D(2L), D(2S), and D3 receptors. Measurement of [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), pEC50 = 6.63, E(max) = 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 D(2S) receptors. Ligand efficacy and selectivity between D(2S) and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antipsychotic Agents / chemical synthesis*
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Antipsychotic Agents / chemistry
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Antipsychotic Agents / pharmacology
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Arrestins / metabolism
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CHO Cells
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Cricetulus
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Drug Partial Agonism
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
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HEK293 Cells
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Heterocyclic Compounds, 2-Ring / chemical synthesis*
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Heterocyclic Compounds, 2-Ring / chemistry
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Heterocyclic Compounds, 2-Ring / pharmacology
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Humans
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Mice
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Molecular Docking Simulation
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Oximes / chemical synthesis*
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Oximes / chemistry
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Oximes / pharmacology
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Radioligand Assay
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Receptors, Dopamine D2 / agonists*
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Receptors, Dopamine D3 / agonists*
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Stereoisomerism
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Structure-Activity Relationship
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Swine
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beta-Arrestin 2
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beta-Arrestins
Substances
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5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)pyrazolo(1,5-a)pyridine-3-carbaldehyde oxime
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ARRB2 protein, human
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Antipsychotic Agents
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Arrb2 protein, mouse
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Arrestins
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Heterocyclic Compounds, 2-Ring
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Oximes
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Piperazines
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Pyrazoles
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Receptors, Dopamine D2
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Receptors, Dopamine D3
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beta-Arrestin 2
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beta-Arrestins
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GTP-Binding Protein alpha Subunits, Gi-Go