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

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Abstract
γ-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABAB receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABAB 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 [3H]NCS-382 [5-[3H]-(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7] annulen-6-ylidene) ethanoic acid] from GHB receptors at concentrations that do not markedly affect [3H]GABA binding to GABAB receptors. 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 (γ-butyrolactone and 1,4-butanediol) and GABAB receptor agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABAB receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABAB 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 mediated by GABAB receptors. Ataxia that was observed with UMB86, UMB72, UMB73, and 3-HPA was not antagonized by CGP35348, suggesting that ataxia induced by these analogs is not mediated by GABAB receptors and might involve GHB receptors.