title: A tertiary alcohol analog of gamma-hydroxybutyric acid as a specific gamma-hydroxybutyric acid receptor ligand.
abstract: gamma-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 [(3)H]NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) 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) >100 microM) 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 GABA-active 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD 21201, USA.
authors.forename: Huifang
authors.initials: H
authors.lastname: Wu
authors.forename: Nick
authors.initials: N
authors.lastname: Zink
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Carter
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Mehta
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Hernandez
authors.forename: Maharaj K
authors.initials: MK
authors.lastname: Ticku
authors.forename: Richard
authors.initials: R
authors.lastname: Lamb
authors.forename: Charles P
authors.initials: CP
authors.lastname: France
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001567:Benzocycloheptenes; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D012055:Reinforcement Schedule; D012978:Sodium Oxybate / Q000031:analogs & derivatives*
chemical_list: C474252:4-hydroxy-4-methylpentanoic acid; C039403:4-hydroxybutyric acid receptor; D001567:Benzocycloheptenes; D008024:Ligands; D010421:Pentanoic Acids; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; D018079:Receptors, GABA; C066471:NCS 382; D012978:Sodium Oxybate