3-Chloropropanoic acid (UMB66): A ligand for the gamma-hydroxybutyric acid receptor lacking a 4-hydroxyl group

Alba T. Macias, R. Jason Hernandez, Ashok K. Mehta, Alexander D. MacKerell, Maharaj K. Ticku, Andrew Coop

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Gamma-Hydroxybutyric acid (GHB) has gained in notoriety in recent years due to its association with sexual assaults. GHB is an endogenous ligand for GHB receptors, but its complete pharmacological mechanism of action in vivo remains unclear due to apparent GABAergic components. It has been proposed that the hydroxyl group in the 4-position acts as a hydrogen bond donor to the GHB receptor. Herein we show that 3-chloropropanoic acid possesses significant affinity for the GHB receptor, has no affinity for GABA receptors, and cannot undergo metabolism to GABAergic compounds. UMB66 is thus a selective agent for the study of GHB in vivo. These results, in combination with data from quantum mechanical calculations, suggest that the hydroxyl group of GHB actually acts as a hydrogen bond acceptor in contrast to the currently accepted model. This finding is anticipated to facilitate the rational design of novel agents with selectivity for GHB receptors that may be used to elucidate the mechanism of action of this common drug of abuse.

Original languageEnglish (US)
Pages (from-to)1643-1647
Number of pages5
JournalBioorganic and Medicinal Chemistry
Issue number7
StatePublished - Apr 1 2004
Externally publishedYes


  • Alcohol
  • Modelling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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