Functionally selective dopamine D₂, D₃ receptor partial agonists

J Med Chem. 2014 Jun 12;57(11):4861-75. doi: 10.1021/jm5004039. Epub 2014 May 23.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology
  • Arrestins / metabolism
  • CHO Cells
  • Cricetulus
  • Drug Partial Agonism
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • HEK293 Cells
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Oximes / chemical synthesis*
  • Oximes / chemistry
  • Oximes / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Radioligand Assay
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D3 / agonists*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swine
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • 5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)pyrazolo(1,5-a)pyridine-3-carbaldehyde oxime
  • ARRB2 protein, human
  • Antipsychotic Agents
  • Arrb2 protein, mouse
  • Arrestins
  • Heterocyclic Compounds, 2-Ring
  • Oximes
  • Piperazines
  • Pyrazoles
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • beta-Arrestin 2
  • beta-Arrestins
  • GTP-Binding Protein alpha Subunits, Gi-Go