Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol

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

Standard

Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol. / Frølund, Bente; Kristiansen, Uffe; Brehm, Lotte; Hansen, Annette B.; Krogsgaard-Larsen, Povl; Falch, Erik.

In: Journal of Medicinal Chemistry, Vol. 38, No. 17, 01.08.1995, p. 3287-3296.

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

Harvard

Frølund, B, Kristiansen, U, Brehm, L, Hansen, AB, Krogsgaard-Larsen, P & Falch, E 1995, 'Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol', Journal of Medicinal Chemistry, vol. 38, no. 17, pp. 3287-3296. https://doi.org/10.1021/jm00017a014

APA

Frølund, B., Kristiansen, U., Brehm, L., Hansen, A. B., Krogsgaard-Larsen, P., & Falch, E. (1995). Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol. Journal of Medicinal Chemistry, 38(17), 3287-3296. https://doi.org/10.1021/jm00017a014

Vancouver

Frølund B, Kristiansen U, Brehm L, Hansen AB, Krogsgaard-Larsen P, Falch E. Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol. Journal of Medicinal Chemistry. 1995 Aug 1;38(17):3287-3296. https://doi.org/10.1021/jm00017a014

Author

Frølund, Bente ; Kristiansen, Uffe ; Brehm, Lotte ; Hansen, Annette B. ; Krogsgaard-Larsen, Povl ; Falch, Erik. / Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 17. pp. 3287-3296.

Bibtex

@article{4f5ad59245a440c0859d91dae4394057,
title = "Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol",
abstract = "5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAa agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAa agonist. A number of compounds bioisosterically derived from 10, including 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-ol (12), 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isoxazol-3-ol (13), and 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isothiazol-3-ol (14), were synthesized and tested as GABAa receptor ligands. Whereas none of these compounds significantly affected GABAb receptor binding or GABA uptake, they showed affinities for GABAa receptor sites in the low-micromolar range. Using cultured cerebral cortical neurons and whole-cell patch-clamp techniques, the efficacies of these compounds relative to that of the full GABAa agonist, isoguvacine (8) (20 μM), were determined. The relative efficacy of 11, which has a higher receptor affinity (IC50 = 1.3 ± 0.3 μM) than 10 (IC50 = 9.3 ± 2.6 μM), was comparable with that of 10 (30-35%). The tetrahydropyridine analog of 10, compound 13, showed a markedly lower receptor affinity (IC50 = 32 ± 10 μM) and apparently a lower relative efficacy than 10. The corresponding unsaturated analog of 11, compound 14, showed a slightly weaker receptor affinity (IC50 = 4.0 ± 2.0 μM) but a significantly higher relative efficacy (5055%) than 11. The 5-isoxazolol isomer of 10, compound 12, showed a reduced receptor affinity (IC50 = 26 ± 7 μM) and a very low relative efficacy. Substitution of propanoic or propenoic acid moieties for the acidic heterocyclic units of these compounds gave the monocyclic amino acids 15-18, which have very little or no affinity for GABAA receptor sites.",
author = "Bente Fr{\o}lund and Uffe Kristiansen and Lotte Brehm and Hansen, {Annette B.} and Povl Krogsgaard-Larsen and Erik Falch",
year = "1995",
month = aug,
day = "1",
doi = "10.1021/jm00017a014",
language = "English",
volume = "38",
pages = "3287--3296",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

RIS

TY - JOUR

T1 - Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol

AU - Frølund, Bente

AU - Kristiansen, Uffe

AU - Brehm, Lotte

AU - Hansen, Annette B.

AU - Krogsgaard-Larsen, Povl

AU - Falch, Erik

PY - 1995/8/1

Y1 - 1995/8/1

N2 - 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAa agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAa agonist. A number of compounds bioisosterically derived from 10, including 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-ol (12), 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isoxazol-3-ol (13), and 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isothiazol-3-ol (14), were synthesized and tested as GABAa receptor ligands. Whereas none of these compounds significantly affected GABAb receptor binding or GABA uptake, they showed affinities for GABAa receptor sites in the low-micromolar range. Using cultured cerebral cortical neurons and whole-cell patch-clamp techniques, the efficacies of these compounds relative to that of the full GABAa agonist, isoguvacine (8) (20 μM), were determined. The relative efficacy of 11, which has a higher receptor affinity (IC50 = 1.3 ± 0.3 μM) than 10 (IC50 = 9.3 ± 2.6 μM), was comparable with that of 10 (30-35%). The tetrahydropyridine analog of 10, compound 13, showed a markedly lower receptor affinity (IC50 = 32 ± 10 μM) and apparently a lower relative efficacy than 10. The corresponding unsaturated analog of 11, compound 14, showed a slightly weaker receptor affinity (IC50 = 4.0 ± 2.0 μM) but a significantly higher relative efficacy (5055%) than 11. The 5-isoxazolol isomer of 10, compound 12, showed a reduced receptor affinity (IC50 = 26 ± 7 μM) and a very low relative efficacy. Substitution of propanoic or propenoic acid moieties for the acidic heterocyclic units of these compounds gave the monocyclic amino acids 15-18, which have very little or no affinity for GABAA receptor sites.

AB - 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAa agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAa agonist. A number of compounds bioisosterically derived from 10, including 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-ol (12), 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isoxazol-3-ol (13), and 5-(1, 2, 3, 6-tetrahydropyrid-4-yl)isothiazol-3-ol (14), were synthesized and tested as GABAa receptor ligands. Whereas none of these compounds significantly affected GABAb receptor binding or GABA uptake, they showed affinities for GABAa receptor sites in the low-micromolar range. Using cultured cerebral cortical neurons and whole-cell patch-clamp techniques, the efficacies of these compounds relative to that of the full GABAa agonist, isoguvacine (8) (20 μM), were determined. The relative efficacy of 11, which has a higher receptor affinity (IC50 = 1.3 ± 0.3 μM) than 10 (IC50 = 9.3 ± 2.6 μM), was comparable with that of 10 (30-35%). The tetrahydropyridine analog of 10, compound 13, showed a markedly lower receptor affinity (IC50 = 32 ± 10 μM) and apparently a lower relative efficacy than 10. The corresponding unsaturated analog of 11, compound 14, showed a slightly weaker receptor affinity (IC50 = 4.0 ± 2.0 μM) but a significantly higher relative efficacy (5055%) than 11. The 5-isoxazolol isomer of 10, compound 12, showed a reduced receptor affinity (IC50 = 26 ± 7 μM) and a very low relative efficacy. Substitution of propanoic or propenoic acid moieties for the acidic heterocyclic units of these compounds gave the monocyclic amino acids 15-18, which have very little or no affinity for GABAA receptor sites.

UR - http://www.scopus.com/inward/record.url?scp=0029150501&partnerID=8YFLogxK

U2 - 10.1021/jm00017a014

DO - 10.1021/jm00017a014

M3 - Journal article

C2 - 7650683

AN - SCOPUS:0029150501

VL - 38

SP - 3287

EP - 3296

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -

ID: 312699272