3-chloropropanoic acid (UMB66): a ligand for the gamma-hydroxybutyric acid receptor lacking a 4-hydroxyl group.
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.
Macias
Alba T
AT
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Room 637, Baltimore, MD 21201, USA.
Hernandez
R Jason
RJ
Mehta
Ashok K
AK
MacKerell
Alexander D
AD
Ticku
Maharaj K
MK
Coop
Andrew
A
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D011422:Propionates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
C039403:4-hydroxybutyric acid receptor; D008024:Ligands; D011422:Propionates; D011956:Receptors, Cell Surface; D018079:Receptors, GABA; C007022:3-chloropropionic acid