Stereoselectivity of NCS-382 binding to γ-hydroxybutyrate receptor in the rat brain

Castelli, Paola; Mocci, Ignazia; Pistis, Marco; Peis, Michela; Berta, Daniela; Gelain, Arianna; Gessa, Gian Luigi; Cignarella, Giorgio

doi:10.1016/s0014-2999(02)01713-2

Cited by 21 publications

(20 citation statements)

References 20 publications

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“…In the two novel GHB structures, the ␣ and ␥ carbons of GHB are locked in a ring for the first time, and the R-isomer of the cyclopentene derivative HOCPCA has as much as 39 times higher affinity than GHB, indicating that this structure closely mimics the bioactive conformation of the endogenous ligand. Similar to HOCPrCA and in accordance with the observations made by Castelli et al (2002) for NCS-382, the new analogs bind to the GHB receptor in a stereoselective manner. Thus, the alignment of GHB at its specific recognition sites is essentially solved and the structural preferences of the receptor in this vicinity are largely mapped out, with the corollary that GHB most likely takes on a different conformation when binding to GABA B receptors.…”

Section: Discussionsupporting

confidence: 85%

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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Section: Discussionsupporting

confidence: 85%

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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“…Pretreatment with NCS-382 has been reported to increase the rate-suppressing effects of GHB on operant behavior and also to suppress rates when administered alone (Carter et al 2004;Cook et al 2002). Castelli et al (2002) suggest NCS-382 may block GHB receptor-mediated effects by acting as an antagonist at an allosteric binding site where GHB is acting to modulate GABA-B receptors. The conflicting reports of NCS-382 antagonism of GHB effects, the variable effects of NCS-382 across studies, subjects, and doses, and the apparent enhancement of some GHB effects indicate that NCS-382 may not act as a neutral GHB antagonist in vivo.…”

Section: Discussionmentioning

confidence: 89%

“…NCS-382 does not displace the GABA-B agonist baclofen from GABA-B receptor sites (Castelli et al 2002). NCS-382 blocked GHB-induced absence seizures in monkeys (Snead 1996).…”

Section: Discussionmentioning

confidence: 92%

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Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons

2005

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“…1) and at GABA receptors. [ 3 H]NCS-382 is used to specifically label GHB binding sites over GABA sites because it displays nanomolar affinity for GHB binding sites but has no affinity for GABA B receptors (Mehta et al, 2001;Castelli et al, 2002;Kaupmann et al, 2003). Furthermore, [ 3 H]NCS-382 displays a regional distribution of binding sites in the brain that is convincingly overlapping with high-affinity [ 3 H]GHB sites, characterized by a particularly high density in the hippocampus and cortex and a very low density in the cerebellum, which is also markedly different from the distribution of GABA B receptors (Snead, 1996;Castelli et al, 2000;Gould et al, 2003;Kaupmann et al, 2003;Wu et al, 2004).…”

mentioning

confidence: 99%

Novel Radioiodinated γ-Hydroxybutyric Acid Analogues for Radiolabeling and Photolinking of High-Affinity γ-Hydroxybutyric Acid Binding Sites

Wellendorph¹,

Høg²,

Sabbatini³

et al. 2010

J Pharmacol Exp Ther

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␥-Hydroxybutyric acid (GHB) is a therapeutic drug, a drug of abuse, and an endogenous substance that binds to low-and high-affinity sites in the mammalian brain. I]BnOPh-GHB) binds to one site in rat brain cortical membranes with low nanomolar affinity (K d , 7 nM; B max , 61 pmol/mg protein). The binding is inhibited by GHB and selected analogs, but not by ␥-aminobutyric acid. Autoradiography using horizontal slices from rat brain demonstrates the highest density of binding in hippocampus and cortical regions and the lowest density in the cerebellum. Altogether, the findings correlate with the labeling and brain regional distribution of highaffinity GHB sites or [

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Stereoselectivity of NCS-382 binding to γ-hydroxybutyrate receptor in the rat brain

Cited by 21 publications

References 20 publications

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

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

Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons

Novel Radioiodinated γ-Hydroxybutyric Acid Analogues for Radiolabeling and Photolinking of High-Affinity γ-Hydroxybutyric Acid Binding Sites

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