␥-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABA B receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA B receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (3-HPA), and 4-hydroxy-4-phenylbutyric acid as compounds that displace In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA up to doses that decreased responding. In mice, GHB, GHB precursors (␥-butyrolactone and 1,4-butanediol) and GABA B receptor agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA B receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABA B receptor agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being

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Tautomerism of neutral xanthine and alloxanthine has been examined both in the gas phase and in aqueous solution. The tautomeric preference in the gas phase has been studied by means of semiempirical and ab initio quantum-mechanical computations with inclusion of correlation effects at the Møller-Plesset level, and from density-functional calculations. The influence of solvent on the relative stability between tautomers has been estimated from self-consistent reaction field calculations performed with different models. The results provide a detailed picture of tautomerism for these biologically relevant purine bases. The functional implications in the recognition by xanthine oxidase are analyzed from inspection of the interaction patterns of the most stable tautomeric forms. A model for the recognition of these purine derivatives in the enzyme binding site is discussed.

␥-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...

Gamma-hydroxybutyric acid (GHB) is a drug of abuse, a therapeutic, and purportedly a neurotransmitter with a complex mechanism of action in vivo due to direct actions at GABA(B) as well as GHB receptors and because of its metabolism to GABA. Herein, we describe 3-ethers of 3-hydroxyphenylacetic acid, which have relatively high affinity at GHB sites, no significant affinity at GABA receptors, and would not be expected to be rapidly metabolized to GABAergic ligands. The selectivity of these compounds (UMB108, UMB109, and UMB119) could prove to be useful for studying the biology of GHB receptors, free from GABAergic effects.