Novel γ-hydroxybutyric acid (GHB) analogs share some, but not all, of the behavioral effects of GHB and GABA_B receptor agonists

γ-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 [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 GABA_B 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 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 mediated by GABA_B 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 GABA _B receptors and might involve GHB receptors.