ChemInform Abstract: ANALGESIC GABA AGONISTS. SYNTHESIS AND STRUCTURE‐ACTIVITY STUDIES ON ANALOGS AND DERIVATIVES OF MUSCIMOL AND THIP

Haefliger, W.; Révész, Láśzló; Maurer, Roland; Roemer, D.; Buescher, H. H.

doi:10.1002/chin.198434206

Cited by 4 publications

(20 citation statements)

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“…However, we soon realized that introduction of substituents at this unfunctionalized sp 3 -carbon in the bicyclic ring system was synthetically unfeasible. Since previous reports suggest that ligands for the orthosteric binding site at GABA A receptors are sensitive to steric hindrance in proximity of the cationic moiety of the molecules, we instead focused on improving selectivity via N -alkylation of bicyclo-GABA ( Krogsgaard-Larsen and Johnston, 1978 ; Haefliger et al, 1984 ; Falch et al, 1986 ; Petersen et al, 2014 ). Given the limited space predicted by the homology model ( Figure 2E ), only small substituents such as methyl were included.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the docking and MD studies, as well as what was chemically feasible, we identified the amino group of bicyclo-GABA and carbon 2 (C2) of 1 as possible sites for derivatization. Although our homology models predicted only limited space at the amino group of bicyclo-GABA, we found this derivatization site particularly interesting because previous studies have reported steric hindrance in the proximity of the cationic moiety of GABA A ligands to decrease agonistic activity (Krogsgaard-Larsen and Johnston, 1978;Haefliger et al, 1984;Falch et al, 1986;Petersen et al, 2014). Derivatization at C2 of 1 was chosen because of its proximity to the extracellular lid according to the docking studies that possibly allows bulky substituents to extend into the extracellular vestibule.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1

et al. 2021

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The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1S,2S,5R)-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [3H]GABA radioligand uptake assays at the four human GATs recombinantly expressed in mammalian cell lines, we identified bicyclo-GABA and its N-methylated analog (2) as the most potent and selective BGT1 inhibitors. Additional pharmacological characterization in a fluorescence-based membrane potential assay showed that bicyclo-GABA and 2 are competitive inhibitors, not substrates, at BGT1, which was validated by a Schild analysis for bicyclo-GABA (pKB value of 6.4). To further elaborate on the selectivity profile both compounds were tested at recombinant α1β2γ2 GABAA receptors. Whereas bicyclo-GABA showed low micromolar agonistic activity, the N-methylated 2 was completely devoid of activity at GABAA receptors. To further reveal the binding mode of bicyclo-GABA and 2 binding hypotheses of the compounds were obtained from in silico-guided mutagenesis studies followed by pharmacological evaluation at selected BGT1 mutants. This identified the non-conserved BGT1 residues Q299 and E52 as the molecular determinants driving BGT1 activity and selectivity. The binding mode of bicyclo-GABA was further validated by the introduction of activity into the corresponding GAT3 mutant L314Q (38 times potency increase cf. wildtype). Altogether, our data reveal the molecular determinants for the activity of bicyclic GABA analogs, that despite their small size act as competitive inhibitors of BGT1. These compounds may serve as valuable tools to selectively and potently target BGT1 in order to decipher its elusive pharmacological role in the brain and periphery such as the liver and kidneys.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1

et al. 2021

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“…Structure−activity relationship of 4-aminomethyl-1-hydroxypyrazole analogues of muscimol and the early report on THIP illustrate the structural limitations. 12,13 However, for IAA, we found that subtle changes, such as a methyl group in specific positions, were allowed and able to induce diverse pharmacological changes in regard to the selectivity. 14,15 2-Aminothiazole-4-acetic acid (1), structurally related to IAA, shows very low affinity for GABA A Rs.…”

Section: ■ Introductionmentioning

confidence: 93%

“…Melting points were recorded on an SRS OptiMelt apparatus in open capillary tubes and are uncorrected. 1 H and 13 C NMR data were recorded on a Bruker Avance 400 MHz spectrometer equipped with a 5 mm PABBO BB[ 1 H, 19 F] Z-GRD probe, or a Bruker Avance 600 MHz spectrometer equipped with a cryogenically cooled 5 mm CPDCH 13 C[ 1 H] Z-GRD probe, at 300 K. Data are tabulated in the following order: chemical shift (δ) [multiplicity (br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet)]; coupling constant(s) J (Hz); and number of protons. The solvent residual peak was used as internal reference.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Five-Membered N-Heterocyclic Scaffolds as Novel Amino Bioisosteres at γ-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

et al. 2019

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Given the heterogeneity within the γ-aminobutyric acid (GABA) receptor and transporter families, a detailed insight into the pharmacology is still relatively sparse. To enable studies of the physiological roles governed by specific receptor and transporter subtypes, a series of GABA analogues comprising five-membered nitrogen- and sulfur-containing heterocycles as amine bioisosteres were synthesized and pharmacologically characterized at native and selected recombinant GABAA receptors and GABA transporters. The dihydrothiazole and imidazoline analogues, 5–7, displayed moderate GAT activities and GABAA receptor binding affinities in the mid-nanomolar range (K i, 90–450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABAA-αβγ receptors but somewhat lower potency as partial agonists at the GABAA-ρ1 receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABAA-αβγ receptors but not the GABAA-ρ1 receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy.

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“…With the exception of thio-THIP, which is a very weak GABA-A agonist [Krogsgaard-Larsen et al, 19831 (Fig. 5), none of these THIP analogues show significant GABA-A receptor affinities. C-alkylated analogues are virtually devoid of affinity for GABA-A receptors [Haefliger et al, 1984;Krogsgaard-Larsen et al, 19881, suggesting that the GABA-A receptors do not recognize and bind a limited part of the molecule of THIP but rather the entire molecule.…”

Section: Thip and Analoguesmentioning

confidence: 99%

GABA‐A agonists and GABA uptake inhibitors: Structure‐activity relationships

Falch

Larsson

Schousboe

et al. 1990

Drug Development Research

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Muscimol is a potent but non-selective GABA-A agonist. Structure-activity studies on the (S)-and (/?)-forms of chiral muscimol analogues have disclosed a high degree of agonist stereoselectivity of the GABA-A receptors. THlP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-01) is a specific GABA-A agonist, which has been the subject of clinical studies in different groups of patients. Even minor alterations of the structure of THlP result in substantial or complete loss of GABA-A agonist activity. 4-PIOL (5-(4-piperidyl)isoxazol-3-ol) shows in vivo GABA-A agonist activity on spinal neurones, whereas the in vitro pharmacological effects in brain tissue preparations are consistent with a GABA-A antagonist profile of 4-PIOL in the brain. Whereas nipetcotic acid and related GABA uptake inhibitors are substrates for the neuronal and glial transport carriers, the glia-selective GABA uptake inhibitors THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol) and probably also THAO (5,6,7, 8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-oI) are not being transported by the glial uptake carrier. Introduction of the DPB (4,4-diphenyl-3-butenyl) or BEE (benzhydryl ethyl ether) substituents on the basic nitrogen atoms of GABA uptake inhibitors, including nipecotic acid and THPO, results in markedly more potent inhibitors. However, unlike THPO, N-DPB-THPO interacts non-selectively with neuronal and glial GABA uptake, and, in contrast to nipecotic acid, N-DPB-nipecotic acid (SKF-89976-A) has been shown not to be transported by the neuronal or glial GABA carriers. Whereas N-DPB-and N-BEE-GABA are weak inhibitors of synaptosomal GABA uptake, N-methylation of these compounds gives potent uptake inhibitors.

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ChemInform Abstract: ANALGESIC GABA AGONISTS. SYNTHESIS AND STRUCTURE‐ACTIVITY STUDIES ON ANALOGS AND DERIVATIVES OF MUSCIMOL AND THIP

Cited by 4 publications

References 0 publications

Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1

Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1

Five-Membered N-Heterocyclic Scaffolds as Novel Amino Bioisosteres at γ-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters

GABA‐A agonists and GABA uptake inhibitors: Structure‐activity relationships

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