A Novel Class of Potent 3-Isoxazolol GABA<sub>A</sub>Antagonists:  Design, Synthesis, and Pharmacology

Frølund, Bente; Tagmose, Lena; Liljefors, Tommy; Stensbøl, Tine B.; Engblom, Christine; Kristiansen, Uffe; Krogsgaard‐Larsen, Povl

doi:10.1021/jm000371q

Cited by 36 publications

(65 citation statements)

References 26 publications

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“…Therefore, the drop in affinity of 8 compared to 7 might be attributed to a steric repulsion between C 4 and the complementary receptor site. Quite similarly, the low affinity observed for 4-methylmuscimol (IC 50 Ͼ 100 µ) [24] in comparison with muscimol had been mainly attributed to a steric bump of the methyl group located in position 4. Indeed, the C 4 of 8 is located in the space occupied by the 4-methyl group of 4-methylmuscimol, as clearly shown by superimposing their populated conformations (Figure 3, B).…”

Section: Resultsmentioning

confidence: 96%

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ²‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

et al. 2006

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A series of 3‐hydroxy‐ and 3‐carboxy‐Δ2‐isoxazoline amino acids, structurally related to the GABAA agonist THIP and to the GABA uptake inhibitors THPO and exo‐THPO, was prepared by means of synthetic strategies involving the 1,3‐dipolar cycloaddition of nitrile oxides. All derivatives were submitted to a pharmacological investigation at both GABA receptors and transporters. Unfortunately, all amino acids were devoid of activity except for a very low affinity at GABAA receptors, displayed by compounds 8 and 17. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Section: Resultsmentioning

confidence: 96%

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ²‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

et al. 2006

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“…So far, drug discovery efforts have relied mainly on indirect structural insight from focused [8]–[12] or unified pharmacophore models recapitulating the structure-activity relationships (SAR) of compounds synthesized during more than fifty years of active medicinal chemistry research in the field [13], [14]. Homology models, on the other hand, have had little practical impact on the design process despite a number of models reported in the literature [15]–[25].…”

Section: Introductionmentioning

confidence: 99%

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

et al. 2013

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We present a full-length α1β2γ2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α1R66, β2T202, α1T129, β2E155, β2Y205 and the backbone of β2S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α1R66, β2T202, α1T129, β2E155, β2Y205 and β2F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β2S156 and β2Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α1T206 and γ2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α1H101 and the N-methyl group near α1Y159, α1T206, and α1Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABAA receptor is made available as Model S1.

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“…The conclusion was that the 3-isoxazolol heterocycles of 4-PIOL and THIP are not at identical positions in the binding sites. Further results demonstrated that the flexible side chain of the arginine R66 in the α 1 subunit might enable the binding pocket to adapt to different bioactive conformations of ligands54.…”

Section: Discussionmentioning

confidence: 93%

“…They mainly investigated the influence of substituents at position 4 of the 3-isoxazolol ring39, 54. In these studies, small aliphatic and also bulky aromatic substituents were tolerated.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of GABA_AReceptor Agonists and Evaluation of their α-Subunit Selectivity and Orientation in the GABA Binding Site

et al. 2008

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Drugs used to treat various disorders target GABAA receptors. To develop α subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [3H]muscimol binding and in patch-clamp experiments with heterologously expressed GABAA αiβ3γ2 receptors (i = 1–6). The effects of 5-aminomethyl-3H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all α subunit isoforms. 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-one 5a and 5-piperidin-4-yl-3H- [1,3,4]oxadiazol-2-thione 6a were weak agonists at α3–, α3–, and α5–containing receptors. When coapplied with GABA they were antagonistic inα2–, α4–, and α6–containing receptors and potentiated α3-containing receptors. 6a protected GABA binding site cysteine-substitution mutants α1F64C and α1S68C from reacting with methanethiosulfonate-ethylsulfonate. 6a specifically covalently modified the α1R66C thiol, in the GABA binding site, through its oxadiazolethione sulfur. These results demonstrate the feasibility of synthesizing α subtype selective GABA mimetic drugs.

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A Novel Class of Potent 3-Isoxazolol GABA_AAntagonists: Design, Synthesis, and Pharmacology

Cited by 36 publications

References 26 publications

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ²‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ²‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

Synthesis of GABA_AReceptor Agonists and Evaluation of their α-Subunit Selectivity and Orientation in the GABA Binding Site

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A Novel Class of Potent 3-Isoxazolol GABAAAntagonists: Design, Synthesis, and Pharmacology

Cited by 36 publications

References 26 publications

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ2‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ2‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

Synthesis of GABAAReceptor Agonists and Evaluation of their α-Subunit Selectivity and Orientation in the GABA Binding Site

Contact Info

Product

Resources

About

A Novel Class of Potent 3-Isoxazolol GABA_AAntagonists: Design, Synthesis, and Pharmacology

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ²‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

Synthesis of 3‐Hydroxy‐ and 3‐Carboxy‐Δ²‐isoxazoline Amino Acids and Evaluation of Their Interaction with GABA Receptors and Transporters

Synthesis of GABA_AReceptor Agonists and Evaluation of their α-Subunit Selectivity and Orientation in the GABA Binding Site