Syntheses and GABA uptake properties of 6-ether- and 6-enol ether-substituted nipecotic acids

N'Goka, Victor; Bissantz, Caterina; Bisel, Philippe; Stenbøl, Tine B.; Krogsgaard‐Larsen, Povl; Schlewer, Gilbert

doi:10.1016/j.ejmech.2004.03.006

Cited by 7 publications

(4 citation statements)

References 17 publications

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“…All these selective and potent GAT1 inhibitors possess a hydrophilic amino acid “head” and a lipophilic aromatic moiety that is connected to the amino acid via a spacer originating from the amino nitrogen of the amino acid. There have been extensive efforts − to develop analogous GAT1 inhibitors with a different substitution pattern of the cyclic amino acid. For example, 4-substituted nipecotic acid derivatives including compound rac - 8 and 6-substituted guvacine derivatives including compound 9 were synthesized and tested for their inhibitory potencies of the GABA transport.…”

Section: Introductionmentioning

confidence: 99%

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

et al. 2018

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This study describes the screening of dynamic combinatorial libraries based on nipecotic acid as core structure with substituents attached to the 5- instead of the common 1-position for the search of novel inhibitors of the GABA transporter GAT1. The generated pseudostatic hydrazone libraries included a total of nearly 900 compounds and were screened for their binding affinities toward GAT1 in competitive mass spectrometry (MS) based Binding Assays. Characterization of the hydrazones with the highest affinities (with cis-configured rac-16gf bearing a 5-(1-naphthyl)furan-2-yl residue and a four atom spacer being the most potent) in binding and uptake experiments revealed an allosteric interaction at GAT1, which was not reported for any other nipecotic acid derivative up to now. Therefore, the herein introduced 5-substituted nipecotic acid derivatives could serve as valuable tools for investigations of allosterically modulated GABA transport mediated by GAT1 and furthermore as starting point for a new class of GAT1 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

et al. 2018

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“…For instance, pyridines 243 undergo reduction with NaBH 4 to give mixtures of the corresponding 1,4-(244) and1,2-dihydropyridines (245) (Scheme 16.78) [199].Also,the pyridine ring of compound 246 has been fully reduced by treatment with NaBH 3 CN, leading to a cis-trans diastereomeric mixture of piperidines 247 and 248 [200].…”

Section: Reactivity J1489mentioning

confidence: 99%

Six‐Membered Heterocycles: Pyridines

González‐Bello

Castedo

2011

Modern Heterocyclic Chemistry

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Figure 16.5 Examples of agrochemical pyridine derivatives and their applications.1434j 16 Six-Membered Heterocycles: Pyridines IR DataThe pyridine IR spectrum is quite similar to the corresponding vibrations of benzene. Pyridine has C-H stretching frequencies in the range 3020-3070 cm À1 as well as C¼C and C¼N stretching frequencies at 1590-1660 cm À1 and near 1500 cm À1 . N J 2,3 = 4-6 J 2,4 = 0-2.5 J 2,5 = 0-2.5 2 3 4 5 6 J 2,6 = 0-0.6 J 3,4 = 7-9 J 3,5 = 0.5-2 1436j 16 Six-Membered Heterocycles: Pyridines R + Metal catalyst ∆ R = alkyl, vinyl, aryl Scheme 16.2 16.

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“…Furthermore, Hoesl et al . and N′Goka et al . synthesized 6‐substituted nipecotic acid ( 6 ) derivatives (e.g., compound 11 ).…”

Section: Introductionmentioning

confidence: 99%

MS‐Based Screening of 5‐Substituted Nipecotic Acid Derived Hydrazone Libraries as Ligands of the GABA Transporter 1

2019

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A screening of compound libraries based on nipecotic acid derivatives with lipophilic residues attached to the scarcely explored 5‐position of the core structure was used for the search of new inhibitors of the γ‐aminobutyric acid (GABA) transporter 1 (mGAT1). The generated compound libraries, which were based on hydrazone chemistry commonly used in dynamic combinatorial chemistry but rendered pseudostatic, were screened for their binding affinities toward mGAT1 by means of MS Binding Assays. With nipecotic acid derived hydrazone rac‐16 h [rac‐(3R,5S)‐{5‐[(E)‐2‐{[5‐(2‐phenylethynyl)thiophen‐2‐yl]methylidene}hydrazin‐1‐yl]piperidine‐3‐carboxylic acid}‐sodium chloride (1/2)], one hit was found and evaluated displaying sub‐micromolar potency (pKi=6.62±0.04) and a noncompetitive interaction mode at mGAT1. By bearing a 5‐(2‐phenylethynyl)thiophen‐2‐yl residue attached to the 5‐position of nipecotic acid via a three‐atom spacer, compound rac‐16 h contains a structural moiety so far unprecedented for these kinds of bioactive molecules, and complements novel 5‐substituted nipecotic acid derived ligands of mGAT1 revealed in a recently published screening campaign. This new class of ligands, with an inhibition mode distinct from that of benchmark mGAT1 inhibitors, could serve as research tools for investigations of mGAT1‐mediated GABA transport.

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Syntheses and GABA uptake properties of 6-ether- and 6-enol ether-substituted nipecotic acids

Cited by 7 publications

References 17 publications

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

Six‐Membered Heterocycles: Pyridines

MS‐Based Screening of 5‐Substituted Nipecotic Acid Derived Hydrazone Libraries as Ligands of the GABA Transporter 1

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