γ-Hydroxybutyric acid (GHB) and γ-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence

Wu, Ying; Ali, Saima S.; Ahmadian, Gholamreza; Liu, Chun Che; Wang, Yu Tian; Gibson, K. Michael; Calver, Andrew R.; Francis, Joseph; Pangalos, Menelas N.; Snead, O. Carter

doi:10.1016/j.neuropharm.2004.08.019

Cited by 59 publications

(46 citation statements)

References 32 publications

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“…GHB binds with weak affinity to the GABA B receptor (Mathivet et al, 1997;Lingenhoehl et al, 1999;Wu et al, 2004). Many of the behavioral and physiological effects of GHB seem to reflect weak agonist activity at GABA B receptors, in that they are prevented or attenuated by GABA B receptor antagonists (Carai et al, 2001;Kaupmann et al, 2003;Quéva et al, 2003;Carter et al, 2005;Koek et al, 2007Koek et al, , 2010.…”

Section: Discussionmentioning

confidence: 99%

GABA_B Receptor-Positive Modulators: Brain Region-Dependent Effects

Hensler¹,

Advani²,

Burke³

et al. 2011

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 99%

GABA_B Receptor-Positive Modulators: Brain Region-Dependent Effects

Hensler¹,

Advani²,

Burke³

et al. 2011

J Pharmacol Exp Ther

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“…3 H]GHB and [ 3 H]NCS-382 high-affinity binding sites exist in mammalian brain (Mehta et al, 2001;Gould et al, 2003) and that these remain intact in mice lacking functional GABA B receptors (Kaupmann et al, 2003;Wu et al, 2004), however, stand in favor of a distinct GHB binding site or receptor. This has already been suggested based on the differential expression profile and ontogeny of GABA B and specific GHB binding sites (Snead, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…This, in combination with the presence of high-affinity [ 3 H]GHB binding sites in the brain (Benavides et al, 1982), suggests the existence of a distinct GHB receptor. In further support of this view, brains from GABA B(1) receptor knock-out mice still exhibit [ 3 H]GHB binding (Kaupmann et al, 2003;Wu et al, 2004), demon-strating that GHB and GABA binding sites are separate entities. NCS-382, a synthetic structural analog of GHB and a purported antagonist of the GHB receptor (Castelli et al, 2004), has been shown to compete with [ 3 H]GHB for the high-affinity sites.…”

mentioning

confidence: 86%

Novel Cyclic γ-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain

Wellendorph¹,

Høg²,

Greenwood³

et al. 2005

J Pharmacol Exp Ther

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␥-Hydroxybutyrate (GHB) is a psychotropic compound endogenous to the brain. Despite its potentially great physiological significance, its exact molecular mechanism of action is unknown. GHB is a weak agonist at GABA B receptors, but there is also evidence of specific GHB receptor sites, the molecular cloning of which remains a challenge. Ligands with high affinity and specificity for the reported GHB binding site are needed for pharmacological dissection of the GHB and GABA B effects and for mapping the structural requirements of the GHB receptorligand interactions. For this purpose, we have synthesized and assayed three conformationally restricted GHB analogs for binding against the GHB-specific ligand [3 H]NCS-382 [(E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene-)acetic acid] in rat brain homogenate. The cyclohexene and cyclopentene analogs, 3-hydroxycyclohex-1-enecarboxylic acid [(RS)-HOCHCA] and 3-hydroxycyclopent-1-enecarboxylic acid [(RS)-HOCPCA], were found to be high-affinity GHB ligands, with IC 50 values in the nanomolar range, and had 9 and 27 times, respectively, higher affinity than GHB. The stereoselectively synthesized R,R-isomer of the trans-cyclopropyl GHB analog, HOCPrCA, proved to have 10-fold higher affinity than its enantiomer. Likewise, the R-enantiomers of HOCHCA and HOCPCA selectively inhibited [3 H]NCS-382 binding. The best inhibitor of these, (R)-HOCPCA, has an affinity 39 times higher than GHB and is thus among the best GHB ligands reported to date. Neither of the cycloalkenes showed any affinity (IC 50 Ͼ 1 mM) for GABA A or GABA B receptors. These compounds show excellent potential as lead structures and novel tools for studying specific GHB receptor-mediated pharmacology.

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“…In mammalian brain GHB levels approximate 1-4 µM (Doherty et al, 1978;Snead, 1991), while in Aldh5a1 −/− mice this level rises to ~250 µM (Hogema et al, 2001). This concentration of GHB is still well below that which is believed to activate GABA B receptors (~5 mM; Lingenhoehl et al, 1999;Wu et al, 2004). On the other hand, some of this GHB may interconvert to GABA, as the enzymes responsible for this are still operative (Rumigny et al, 1981), hence elevating the excess GABA due to the block in Aldh5a1 even more (Snead & Gibson, 2005).…”

Section: Role Of Gaba and Ghb In Kd's Mechanismmentioning

confidence: 99%

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

Nylen

Velázquez

Likhodii

et al. 2008

Experimental Neurology

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Succinic semialdehyde dehydrogenase (SSADH) deficiency is an heritable disorder of GABA degradation characterized by ataxia, psychomotor retardation and seizures. To date, there is no effective treatment for SSADH deficiency. We tested the hypothesis that a ketogenic diet (KD) would improve outcome in an animal model of SSADH deficiency, the SSADH knockout mouse (Aldh5a1 −/− ). Using a 4:1 ratio of fat to combined carbohydrate and protein KD we set out to compare the general phenotype, in vivo and in vitro electrophysiology and [ 35 S]TBPS binding in both Aldh5a1 −/− mice and control (Aldh5a1 +/+ ) mice. We found that the KD prolonged the lifespan of mutant mice by >300% with normalization of ataxia, weight gain and EEG compared to mutants fed a control diet. Aldh5a1 −/− mice showed significantly reduced mIPSC frequency in CA1 hippocampal neurons as well as significantly decreased [ 35 S]TBPS binding in all brain areas examined. In KD fed mutants, mIPSC activity normalized and [ 35 S]TBPS binding was restored in the cortex and hippocampus. The KD appears to reverse toward normal the perturbations seen in Aldh5a1 −/− mice. Our data suggest that the KD may work in this model by restoring GABAergic inhibition. These data demonstrate a successful experimental treatment for murine SSADH deficiency using a KD, giving promise to the idea that the KD may be successful in the clinical treatment of SSADH deficiency.

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γ-Hydroxybutyric acid (GHB) and γ-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence

Cited by 59 publications

References 32 publications

GABA_B Receptor-Positive Modulators: Brain Region-Dependent Effects

GABA_B Receptor-Positive Modulators: Brain Region-Dependent Effects

Novel Cyclic γ-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

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γ-Hydroxybutyric acid (GHB) and γ-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence

Cited by 59 publications

References 32 publications

GABAB Receptor-Positive Modulators: Brain Region-Dependent Effects

GABAB Receptor-Positive Modulators: Brain Region-Dependent Effects

Novel Cyclic γ-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

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Resources

About

GABA_B Receptor-Positive Modulators: Brain Region-Dependent Effects

GABA_B Receptor-Positive Modulators: Brain Region-Dependent Effects