Phosphinic Acid Analogs of GABA. 1. New Potent and Selective GABAB Agonists

Froestl, Wolfgang; Mickel, Stuart J.; Hall, Roger G.; Sprecher, G. Von; Strub, Dietrich; Baumann, P.; Brugger, F.; Gentsch, C.; Jaekel, J.

doi:10.1021/jm00017a015

Cited by 190 publications

(121 citation statements)

References 32 publications

(64 reference statements)

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…3-APA and its methylated analog 3-APMPA are selective competitive antagonists for GABA C over GABA A Rs (Johnston, 1996), although they are also GABA B receptor agonists (Froestl et al, 1995). Mutants Y102F, V140L, and FYS240VF exhibited the most dramatic reduction of apparent affinity to the GABA C R competitive antagonist 3-APA (11-, 32-, and 25-fold reduction, respectively, Fig.…”

Section: Resultsmentioning

confidence: 95%

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ₁GABA_CReceptor from GABA_AReceptors

Zhang¹,

Xue²,

Chang³

2008

Mol Pharmacol

View full text Add to dashboard Cite

GABA receptor (GABAR) types C (GABA C R) and A (GABA A R) are both GABA-gated chloride channels that are distinguished by their distinct competitive antagonist properties. The structural mechanism underlying these distinct properties is not well understood. In this study, using previously identified binding residues as a guide, we made individual or combined mutations of nine binding residues in the 1 GABA C R subunit to their counterparts in the ␣ 1 ␤ 2 ␥ 2 GABA A R or reverse mutations in ␣ 1 or ␤ 2 subunits. The mutants were expressed in Xenopus laevis oocytes and tested for sensitivities of GABA-induced currents to the GABA A and GABA C receptor antagonists. The results revealed that bicuculline insensitivity of the 1 GABA C R was mainly determined by Tyr106, Phe138 and Phe240 residues.

show abstract

Section: Resultsmentioning

confidence: 95%

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ₁GABA_CReceptor from GABA_AReceptors

Zhang¹,

Xue²,

Chang³

2008

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…ϭ 212-214°C). SKF97541 and CGP35348 were synthesized as described previously (Froestl et al, 1995). The radioligand […”

Section: Methodsmentioning

confidence: 99%

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

Carter

Chen

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

␥-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 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 (␥-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

show abstract

“…Compounds studied included GHB (sodium salt), (Ϯ)baclofen, GBL, and 1,4-BDL (Sigma-Aldrich Corp., St. Louis, MO), diazepam (Sigma/ RBI, Natick, MA), flumazenil (a gift from F. Hoffmann-La Roche Ltd., Basel, Switzerland), NCS-382 (sodium salt), and CGP 35348 (sodium salt). NCS-382 and CGP 35348 were synthesized as previously described (Maitre et al, 1990;Froestl et al, 1995). Diazepam was dissolved in vehicle consisting of 70% emulphor, 20% sterile water, and 10% ethanol (by volume).…”

Section: Methodsmentioning

confidence: 99%

Effects of γ-Hydroxybutyrate (GHB) on Schedule-Controlled Responding in Rats: Role of GHB and GABA_B Receptors

Carter¹,

Wu²,

Chen³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

␥-Hydroxybutyrate (GHB), a metabolite of ␥-aminobutyric acid (GABA), is an increasingly popular drug of abuse and was recently approved for the treatment of narcolepsy (Xyrem). GHB and GABA receptors have been implicated in mediating effects of GHB; however, the relative importance of each of these receptors is unclear. This study evaluated the effects of selective antagonists in combination with GHB and related compounds on schedule-controlled responding. Eight male Sprague-Dawley rats responded under a fixed-ratio schedule of food presentation. Cumulative dose-effect curves were generated and ED 50 values calculated to evaluate the relative potency at decreasing responding. The rank-order potency was as follows: diazepam ϭ baclofen Ͼ ␥-butyrolactone (GBL) Ͼ 1,4-butanediol (1,4-BDL) ϭ GHB. All compounds decreased responding 20 min after administration. The duration of action of diazepam, GHB, and GBL was shorter than that of 1,4-BDL and baclofen. p-3-Aminopropyl-p-diethoxymethyl phosphinic acid (CGP 35348) antagonized the rate-decreasing effects of baclofen and not GHB; flumazenil antagonized the effects of diazepam and not GHB. The GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a] [7]annulen-6-ylidene ethanoic acid (NCS-382) did not attenuate the rate-decreasing effects of GHB, baclofen, or diazepam; larger doses of NCS-382 further decreased rate of responding when given in combination with each of these compounds. These studies show that GBL, 1,4-BDL, and GHB differ significantly in potency and duration of action. The ability of CGP 35348 to antagonize the rate-decreasing effects of baclofen may be limited by the involvement of multiple GABA B receptor subtypes and the lack of antagonism of GHB by NCS-382 may be due to its own GHB-like effects.␥-Hydroxybutyrate (GHB) is an endogenous metabolite of ␥-aminobutyric acid (GABA) and a putative neurotransmitter (Roth and Giarman, 1970;Maitre, 1997). GHB binds to GABA B receptors (Mathivet et al., 1997;Lingenhoehl et al., 1999) and specific GHB sites (Benavides et al., 1982;Snead and Liu, 1984;Mehta et al., 2001) in the brain. GHB-specific binding sites (as labeled by [ 3 H]NCS-382) are believed to be G protein-coupled receptors (Snead, 2000). In addition to binding at GHB and GABA B receptors, GHB is metabolized to GABA (Roth and Giarman, 1969), which may act at GABA A , GABA B , and GABA C receptors. Administration of GHB can induce sedation, amnesia, ataxia, catalepsy, absence seizures, coma, and death (Snead and Liu, 1993;Nicholson and Balster, 2001); however, the relative importance of GHB receptors and GABA receptors in mediating these effects is unclear. GHB is an emerging drug of abuse (Nicholson and Balster, 2001;Mason and Kerns, 2002); thus, a GHB antagonist could be clinically useful for treating GHB overdose and toxicity.NCS-382 is a GHB antagonist that blocks some, but not all, of the effects of GHB. NCS-382 binds to GHB receptors in cortex and hippocampus and has no appreciable affinity at GABA A or GABA B receptors (Serra...

show abstract

Phosphinic Acid Analogs of GABA. 1. New Potent and Selective GABAB Agonists

Cited by 190 publications

References 32 publications

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ₁GABA_CReceptor from GABA_AReceptors

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ₁GABA_CReceptor from GABA_AReceptors

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

Effects of γ-Hydroxybutyrate (GHB) on Schedule-Controlled Responding in Rats: Role of GHB and GABA_B Receptors

Contact Info

Product

Resources

About

Phosphinic Acid Analogs of GABA. 1. New Potent and Selective GABAB Agonists

Cited by 190 publications

References 32 publications

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ1GABACReceptor from GABAAReceptors

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ1GABACReceptor from GABAAReceptors

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

Effects of γ-Hydroxybutyrate (GHB) on Schedule-Controlled Responding in Rats: Role of GHB and GABAB Receptors

Contact Info

Product

Resources

About

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ₁GABA_CReceptor from GABA_AReceptors

Structural Determinants for Antagonist Pharmacology That Distinguish the ρ₁GABA_CReceptor from GABA_AReceptors

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

Effects of γ-Hydroxybutyrate (GHB) on Schedule-Controlled Responding in Rats: Role of GHB and GABA_B Receptors