ChemInform Abstract: Synthesis and Pharmacological Evaluation of γ‐Aminobutyric Acid Analogues. New Ligand for GABAB Sites.

Berthelot, Pascal; Vaccher, Claude; Musadad, Amir; Flouquet, Nathalie; Debaert, M.; Luyckx, M.

doi:10.1002/chin.198737311

Cited by 3 publications

(4 citation statements)

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“…Previous results obtained with the 4-hydroxybaclofen analogue showed it was completely inactive in binding GABAb tests. 14 In the present paper, our results suggest also that the substituent in the para position on the aromatic or pseudoaromatic ring should be of lipophilic nature to observe high affinity. The higher activity of thienyl analogues (5c » 5a and 5d » 5b) could be explained by the higher electronegativity of the oxygen atom in comparison with that of the sulfur atom.…”

Section: Discussionsupporting

confidence: 64%

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies

Berthelot¹,

Vaccher²,

Flouquet³

et al. 1991

J. Med. Chem.

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Baclofen (beta-(p-chlorophenyl)-GABA) is a selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds that bind to the GABAB receptor is very important to clarify structural requirements. We report herein the synthesis and the binding studies of variously substituted 3-thienyl- and 3-furylaminobutyric acids. 4-Amino-3-(5-methyl-2-thienyl)butyric acid (5d) and 4-amino-3-(5-chloro-2-thienyl)butyric acid (5h) are potent and specific ligands for GABAB receptor. The IC50 values for the displacement of (R)-(-)-[3H]baclofen are 1.34 and 0.61 microM for 5d and 5h, respectively, as compared to 0.33 microM for baclofen.

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Section: Discussionsupporting

confidence: 64%

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies

Berthelot¹,

Vaccher²,

Flouquet³

et al. 1991

J. Med. Chem.

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“…From the structural analysis of diverse GABA B receptor agonists, we determined that the substitution of the chlorine atom in the para position of the aromatic ring by electron donating groups (R = i ‐Pr, CH 2 C 6 H 5 , CH 2 ‐4‐F‐C 6 H 4 , and CH 2 ‐5‐Cl‐thienyl) generate inactive compounds of general structure 25 (Figure ) (Berthelot et al., ). Substitution of the aromatic ring by benzofuran type groups produced two analogues, 26 and 27 , which in [ 3 H] Baclofen binding assays were active at concentrations of IC 50 = 18 μM and IC 50 = 5.6 μM, respectively (Berthelot et al., ).…”

Section: Resultsmentioning

confidence: 99%

“…These molecules possess the Baclofen pharmacophoric groups and their biological activity was determined in different biological systems. (Attia et al., ; Berthelot et al., , ; Man et al., ).…”

Section: Computational Detailsmentioning

confidence: 99%

In silico structure‐based design of GABA_B receptor agonists using a combination of docking and QSAR

et al. 2019

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The study of γ‐aminobutyric acid B receptor (GABAB) activation is of great interest for several brain disorders. The search of new GABAB receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABAB receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABAB receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABAB receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABAB receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features (ELUMO and T(N…O)) and the energy interaction with GABAB receptor (ETRP278). This model was validated by the QUIK, REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the QLOO, QASYM, R02 and rm2 rules. Finally, six new compounds are proposed (35–40) with high potential to be used as GABAB receptor agonists.

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“…Initial attempts yielded phosphonic and sulfonic acid analogues of baclofen as well as 3-benzo [b] furan-2-yl-GABA derivatives, all of which have relatively low affinities for the receptor and are ineffective following systemic administration [29][30][31][32]. Structure-activity studies with phosphinic GABA B receptor agonists revealed that ethylphosphinic acid, and higher homologues, are receptor antagonists (Figure 2; [16]).…”

Section: Gabab Receptor Antagonistsmentioning

confidence: 99%

GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities

Enna¹

1997

Expert Opinion on Investigational Drugs

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GABA B receptor agonists and antagonists: pharmacological properties and therapeutic possibilities SJ Ennaγ-Aminobutyric acid (GABA), an inhibitory neurotransmitter, is widely distributed throughout the brain and spinal cord. Two major families of GABA receptors have been identified, GABA A and GABAB. While much is known about the pharmacological and molecular properties of GABAA receptors, it is only within the last few years that potent and selective antagonists have been developed for the GABA B site, and only within the past few months that this receptor has been cloned. Thus, tools are now available to define more fully the GABAB receptor in terms of its biology and the therapeutic potential of manipulating this site. Data suggest that, in addition to their established use as muscle relaxants, GABAB receptor agonists possess analgesic and antitussive properties, and may be useful for treating bladder dysfunction. While there is less clinical data on GABA B receptor antagonists, preclinical results indicate that they may be of value in treating absence epilepsy, cognitive dysfunction and, possibly, pulmonary and intestinal disorders. However, for this potential to be fully exploited, it is necessary to identify and characterise molecularly and pharmacologically distinct GABA B receptor subtypes.

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ChemInform Abstract: Synthesis and Pharmacological Evaluation of γ‐Aminobutyric Acid Analogues. New Ligand for GABAB Sites.

Abstract: Reaction of the phenol (I) with the chlorides (II) and subsequent basic ring cleavage yield the amino acids (III).

Cited by 3 publications

References 1 publication

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies

In silico structure‐based design of GABA_B receptor agonists using a combination of docking and QSAR

GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities

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ChemInform Abstract: Synthesis and Pharmacological Evaluation of γ‐Aminobutyric Acid Analogues. New Ligand for GABAB Sites.

Abstract: Reaction of the phenol (I) with the chlorides (II) and subsequent basic ring cleavage yield the amino acids (III).

Cited by 3 publications

References 1 publication

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies

In silico structure‐based design of GABAB receptor agonists using a combination of docking and QSAR

GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities

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In silico structure‐based design of GABA_B receptor agonists using a combination of docking and QSAR