Haloperidol bound D 2 dopamine receptor structure inspired the discovery of subtype selective ligands

Nat Commun. 2020 Feb 26;11(1):1074. doi: 10.1038/s41467-020-14884-y.

Abstract

The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Most clinically approved and investigational drugs that target this receptor are known to be subfamily-selective for all three D2-like receptors, rather than subtype-selective for only DRD2. Here, we report the crystal structure of DRD2 bound to the most commonly used antipsychotic drug, haloperidol. The structures suggest an extended binding pocket for DRD2 that distinguishes it from other D2-like subtypes. A detailed analysis of the structures illuminates key structural determinants essential for DRD2 activation and subtype selectivity. A structure-based and mechanism-driven screening combined with a lead optimization approach yield DRD2 highly selective agonists, which could be used as chemical probes for studying the physiological and pathological functions of DRD2 as well as promising therapeutic leads devoid of promiscuity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / pharmacology*
  • Crystallography, X-Ray
  • Haloperidol / pharmacology*
  • Humans
  • Protein Conformation / drug effects
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D2 / ultrastructure*
  • Risperidone / metabolism
  • Risperidone / pharmacology

Substances

  • Antipsychotic Agents
  • DRD2 protein, human
  • Receptors, Dopamine D2
  • Haloperidol
  • Risperidone