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

Abstract

␥-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 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 [ 3 H]GABA, UMB68 showed no affinity (IC 50 Ͼ100 M) 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 GABAactive 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.␥-Hydroxybutyric acid (GHB) (Fig. 1) is an endogenous compound that was initially thought to simply be an inactive metabolite of GABA. However, findings that GHB appears to normalize sleep patterns in narcoleptic patients (Nishino and Mignot, 1997) and its increasing popularity as a recreational drug (Bernasconi et al., 1999) have led to a recent growth of interest in GHB (Nicholson and Balster, 2001). GHB is concentrated in specific regions of the mammalian brain where specific binding sites or receptors are located and, to a lesser extent, in some peripheral tissues (Nelson et al., 1981;Vayer and Maitre, 1988;Snead, 1996). GHB rapidly crosses into the central nervous system and is also rapidly metabolized (Bernasconi et al., 1999), the latter being a major factor contributing to its very short duration of action. GHB has also been proposed to be an effective treatment for alcohol (Addolorato et al., 2000;Gessa et al., 2000) and opioid dependence (Gallimberti et al., 1994).Although GHB binding sites have been described (Benavides et al., 1982;Snead and Liu, 1984;Hechler et al., 1987;Snead and Nichols, 1987;Castelli et al., 2000, the exact mechanism of action of GHB remains elusive due, in part, to apparent GABA-mediated effects (Carai et al., 2001(Carai et al., , 2002. GHB is known to interact with GABA B receptors with low affinity (Bernasconi et al., 1992;Xie and Smart, 1992;Mathivet et al., 1997;Lingenhoehl et al., 1999), and it has been demonst...

Discriminative stimulus effects of gamma-hydroxybutyrate (GHB) and its metabolic precursor, gamma-butyrolactone (GBL) in rats

“…Several recent studies have employed drug discrimination procedures as an animal model of subjective drug effects to examine the pharmacological mechanisms underlying these effects (Winter 1981;Colombo et al 1995aColombo et al ,b, 1998Lobina et al 1999;Metcalf et al 2001;Carter et al 2003;Wu et al 2003;Baker et al 2004). Relatively few studies, however, have examined the discriminative stimulus effects of the GHB precursors, GBL and BDL.…”

Influence of reinforcer type and route of administration on gamma-hydroxybutyrate discrimination in rats

“…In a review of the neurobehavioral effects of GHB, Nicholson and Balster (2001) concluded that GHB does not appear to have discriminative stimulus properties that are consistently similar to any of the traditional classes of abused drugs. There is now a growing body of literature on the discriminative stimulus effects of GHB, and recent reports Wu et al 2003) suggest that these effects are mediated primarily by GABA B receptors.…”

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABABReceptor Agonists

“…As the dose of GHB is increased, additional mechanisms of action are likely to contribute to its behavioral profile. Thus, GHB or dopamine receptor-mediated mechanisms that do not seem to play a prominent role in the discriminative stimulus effects of GHB in rats (Winter, 1981;Wu et al, 2003;Carter et al, 2004a) could play a more predominant role in mediating the effects of GHB that are observed at larger doses.…”

“…[ 3 H]GABA (10 nM) binding to GABA A receptors in cerebral cortex was performed in a similar manner, using a 10-min incubation period at 4°C, and GABA (100 M) to define nonspecific binding. Binding affinity for GABA B receptors was measured in tissue from cerebellum, an area where GHB binding to GABA B receptors has been shown previously (Mathivet et al, 1997;Wu et al, 2003). For [ 3 H]GABA (10 nM) binding to GABA B receptors in rat cerebellum, all of the assay tubes contained 40 M isoguvacine HCl (MP Biomedicals, Irvine, CA) to displace [ 3 H]GABA binding to GABA A receptors.…”