GABAA agonists: Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide

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Standard

GABAA agonists : Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide. / Frølund, Bente; Jeppesen, Lone; Krogsgaard‐Larsen, Povl; Hansen, Jan J.

In: Chirality, Vol. 7, No. 6, 1995, p. 434-438.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Frølund, B, Jeppesen, L, Krogsgaard‐Larsen, P & Hansen, JJ 1995, 'GABAA agonists: Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide', Chirality, vol. 7, no. 6, pp. 434-438. https://doi.org/10.1002/chir.530070608

APA

Frølund, B., Jeppesen, L., Krogsgaard‐Larsen, P., & Hansen, J. J. (1995). GABAA agonists: Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide. Chirality, 7(6), 434-438. https://doi.org/10.1002/chir.530070608

Vancouver

Frølund B, Jeppesen L, Krogsgaard‐Larsen P, Hansen JJ. GABAA agonists: Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide. Chirality. 1995;7(6):434-438. https://doi.org/10.1002/chir.530070608

Author

Frølund, Bente ; Jeppesen, Lone ; Krogsgaard‐Larsen, Povl ; Hansen, Jan J. / GABAA agonists : Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide. In: Chirality. 1995 ; Vol. 7, No. 6. pp. 434-438.

Bibtex

@article{22c5013af04d4d2ca5547dfd21ad8f05,
title = "GABAA agonists: Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide",
abstract = "(3SR,4RS)‐3,4‐Epoxypiperidine‐4‐carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)‐1‐(benzyloxycarbonyl)‐3,4‐epoxypiperidine‐4‐carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 > 100 μM), (+)‐isoguvacine oxide (IC50 = 0.20 ± 0.03 μM) and (−)‐isoguvacine oxide (IC50 = 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)‐isoguvacine oxide (EC50 = 6 μM; 33% relative efficacy) and (−)‐isoguvacine oxide (EC50 = 5 μM; 38% efficacy relative to 10 μM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor‐associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure—activity studies on GABAA agonists. Thus, the model of the GABAA recognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABAA agonists is assumed to be embedded during receptor activation, may have to be revised. {\textcopyright} 1995 Wiley‐Liss, Inc.",
keywords = "benzodiazepine stimulation, chiral HPLC, enantiomeric purity, GABA agonist, GABA receptor affinity, resolution",
author = "Bente Fr{\o}lund and Lone Jeppesen and Povl Krogsgaard‐Larsen and Hansen, {Jan J.}",
year = "1995",
doi = "10.1002/chir.530070608",
language = "English",
volume = "7",
pages = "434--438",
journal = "Chirality",
issn = "0899-0042",
publisher = "Wiley",
number = "6",

}

RIS

TY - JOUR

T1 - GABAA agonists

T2 - Resolution and pharmacology of (+)‐ and (−)‐isoguvacine oxide

AU - Frølund, Bente

AU - Jeppesen, Lone

AU - Krogsgaard‐Larsen, Povl

AU - Hansen, Jan J.

PY - 1995

Y1 - 1995

N2 - (3SR,4RS)‐3,4‐Epoxypiperidine‐4‐carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)‐1‐(benzyloxycarbonyl)‐3,4‐epoxypiperidine‐4‐carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 > 100 μM), (+)‐isoguvacine oxide (IC50 = 0.20 ± 0.03 μM) and (−)‐isoguvacine oxide (IC50 = 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)‐isoguvacine oxide (EC50 = 6 μM; 33% relative efficacy) and (−)‐isoguvacine oxide (EC50 = 5 μM; 38% efficacy relative to 10 μM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor‐associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure—activity studies on GABAA agonists. Thus, the model of the GABAA recognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABAA agonists is assumed to be embedded during receptor activation, may have to be revised. © 1995 Wiley‐Liss, Inc.

AB - (3SR,4RS)‐3,4‐Epoxypiperidine‐4‐carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)‐1‐(benzyloxycarbonyl)‐3,4‐epoxypiperidine‐4‐carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 > 100 μM), (+)‐isoguvacine oxide (IC50 = 0.20 ± 0.03 μM) and (−)‐isoguvacine oxide (IC50 = 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)‐isoguvacine oxide (EC50 = 6 μM; 33% relative efficacy) and (−)‐isoguvacine oxide (EC50 = 5 μM; 38% efficacy relative to 10 μM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor‐associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure—activity studies on GABAA agonists. Thus, the model of the GABAA recognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABAA agonists is assumed to be embedded during receptor activation, may have to be revised. © 1995 Wiley‐Liss, Inc.

KW - benzodiazepine stimulation

KW - chiral HPLC

KW - enantiomeric purity

KW - GABA agonist

KW - GABA receptor affinity

KW - resolution

UR - http://www.scopus.com/inward/record.url?scp=0028840751&partnerID=8YFLogxK

U2 - 10.1002/chir.530070608

DO - 10.1002/chir.530070608

M3 - Journal article

C2 - 7577350

AN - SCOPUS:0028840751

VL - 7

SP - 434

EP - 438

JO - Chirality

JF - Chirality

SN - 0899-0042

IS - 6

ER -

ID: 312699402