Vol. 305, Issue 2, 675-679, May 2003

A Tertiary Alcohol Analog of -Hydroxybutyric Acid as a Specific -Hydroxybutyric Acid Receptor Ligand

Huifang Wu, Nick Zink, Lawrence P. Carter, Ashok K. Mehta, R. Jason Hernandez, Maharaj K. Ticku , Richard Lamb , Charles P. France and Andrew Coop

Department of Pharmaceutical Sciences (H.W., N.Z., A.C.), University of Maryland, School of Pharmacy, Baltimore, Maryland; Departments of Pharmacology (L.P.C., A.K.M., R.J.H., M.K.T., R.L., C.P.F.) and Psychiatry (M.K.T., R.L., C.P.F), University of Texas Health Science Center at San Antonio, San Antonio, Texas

-Hydroxybutyric acid (GHB) shows great promise as a treatment for sleeping disorders but is also increasingly abused. The exact mechanism of action of GHB is yet to be delineated, but it is known to interact with specific GHB binding sites or receptors, to act as a weak agonist at GABA_B receptors, and that GHB undergoes metabolism to GABA. In drug discrimination studies, GABA_B agonists, and to a lesser extent GABA_A-positive modulators, substitute for GHB. To delineate the relative contributions of each receptor system to the profile of GHB, tertiary alcohol analogs of GHB and its homolog, 5-hydroxypentanoic acid (UMB58), were prepared (UMB68 and UMB75, respectively), which cannot be metabolized to GABA-active compounds. Binding studies against [³H]NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid] showed that the tertiary alcohol analog of GHB (UMB68) has similar affinity to GHB, with the longer chain analogs possessing lower affinity. Against [³H]GABA, UMB68 showed no affinity (IC₅₀ >100 µM) at GABA_A or GABA_B receptors. In vivo studies showed that, at behaviorally active doses, rats trained to discriminate GHB did not recognize the novel ligands as GHB. Thus, UMB68 is a selective GHB receptor ligand in binding assays, will not undergo metabolism to GABA-active compounds, and does not show the same effects as GHB in vivo. These data suggest that, although UMB68 binds to the GHB receptor, it does not have the observed GABA receptor-mediated effects of GHB in vivo and could provide a novel tool for studying the pharmacology of the GHB receptor in the absence of complicating GABAergic effects.