Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure

J Med Chem. 2017 Apr 13;60(7):2908-2929. doi: 10.1021/acs.jmedchem.6b01857. Epub 2017 Mar 22.

Abstract

1,4-Disubstituted aromatic piperazines are privileged structural motifs recognized by aminergic G protein-coupled receptors. Connection of a lipophilic moiety to the arylpiperazine core by an appropriate linker represents a promising concept to increase binding affinity and to fine-tune functional properties. In particular, incorporation of a pyrazolo[1,5-a]pyridine heterocyclic appendage led to a series of high-affinity dopamine receptor partial agonists. Comprehensive pharmacological characterization involving BRET biosensors, binding studies, electrophysiology, and complementation-based assays revealed compounds favoring activation of G proteins (preferably Go) over β-arrestin recruitment at dopamine D2 receptors. The feasibility to design G protein-biased partial agonists as putative novel therapeutics was demonstrated for the representative 2-methoxyphenylpiperazine 16c, which unequivocally displayed antipsychotic activity in vivo. Moreover, combination of the pyrazolo[1,5-a]pyridine appendage with a 5-hydroxy-N-propyl-2-aminotetraline unit led to balanced or G protein-biased dopaminergic ligands depending on the stereochemistry of the headgroup, illustrating the complex structure-functional selectivity relationships at dopamine D2 receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use*
  • Dopamine Agonists / chemistry*
  • Dopamine Agonists / pharmacology
  • Dopamine Agonists / therapeutic use*
  • Drug Discovery
  • GTP-Binding Proteins / metabolism
  • Humans
  • Male
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • beta-Arrestins / metabolism

Substances

  • Antipsychotic Agents
  • Dopamine Agonists
  • Pyrazoles
  • Pyridines
  • Receptors, Dopamine D2
  • beta-Arrestins
  • pyrazolo(3,4-b)pyridine
  • GTP-Binding Proteins