Agonists of the γ-aminobutyric acid type B (GABAB) receptor derived from β-hydroxy and β-amino difluoromethyl ketones

Sowaileh, Munia F.; Salyer, Amy E.; Roy, Kuldeep K.; John, Jinu P.; Woods, James R.; Doerksen, Robert J.; Hockerman, Gregory H.; Colby, David A.

doi:10.1016/j.bmcl.2018.04.003

Cited by 7 publications

(13 citation statements)

References 27 publications

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“…Recently, the difluoromethyl ketone scaffold was identified as a GABA B -R agonist scaffold, and exhibited in vivo activity in mice as potential anxiolytic drugs [101]. Difluoromethyl ketones represent a new chemotype of GABA B -R ligands, but need to be further investigated as many of these compounds are known to bind multiple other targets such as the matrix metalloproteases [101,102].…”

Section: Orthosteric Ligandsmentioning

confidence: 99%

The GABAB Receptor—Structure, Ligand Binding and Drug Development

2020

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The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.

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Section: Orthosteric Ligandsmentioning

confidence: 99%

The GABAB Receptor—Structure, Ligand Binding and Drug Development

2020

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“…However, SAR within this series was also steep, and researchers in the field began to explore alternative pharmacological mechanisms by which to activate the GABA B receptor that would provide novel chemical matter as leads. 76 An attractive approach toward manipulation of the GABA B system is the utilization of positive allosteric modulators (PAMs), as has been demonstrated for other metabotropic GPCRs, such as the metabotropic glutamate receptors. 78,79 PAMs potentiate GABA responses at the GABA B receptor, thus acting only when GABA activates the receptor, avoiding disruption of the physiological cycle of activation.…”

Section: ■ Chemical Properties and Synthesismentioning

confidence: 99%

“…In 2013 and 2018, Colby and co-workers disclosed a fundamentally distinct chemotype of selective GABA B agonists based on a β-hydroxydifluoromethylketone and β-aminodifluoromethylketone scaffolds, and represented by agonists such as 45 and 46 (Figure ). , While ∼10-fold less potent than 3 , this new chemotype was of great interest as it represented a significant structural departure from the prototypical GABA B agonist pharmacophores. At this time, the X-ray structure of the GABA B receptor had been solved as well as the ( R )-baclofen ( 15 )-bound GABA B receptor complex .…”

Section: Medicinal Chemistry and Structure–activity Relationshipsmentioning

confidence: 99%

“…Colby then docked these novel GABA B agonists into the receptor, and data suggest that the ( S )-enantiomers of 45 and 46 should be more active. However, SAR within this series was also steep, and researchers in the field began to explore alternative pharmacological mechanisms by which to activate the GABA B receptor that would provide novel chemical matter as leads …”

Section: Medicinal Chemistry and Structure–activity Relationshipsmentioning

confidence: 99%

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Classics in Chemical Neuroscience: Baclofen

Kent

Park

Lindsley

2020

ACS Chem. Neurosci.

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Baclofen, β-(4-chlorophenyl)-γ-aminobutyric acid, holds a unique position in neuroscience, remaining the only U.S. Food and Drug Administration (FDA) approved GABAB agonist. While intended to be a more brain penetrant, i.e, ability to cross the blood-brain barrier (BBB), version of GABA (γ-aminobutyric acid) for the potential treatment of epilepsy, baclofen’s highly efficacious muscle relaxant properties led to its approval, as a racemate, for the treatment of spasticity. Interestingly, baclofen received FDA approval before its receptor, GABAB, was discovered and its exact mechanism of action was known. In recent times, baclofen has a myriad of off-label uses, with the treatment for alcohol abuse and drug addiction garnering a great deal of attention. This Review aims to capture the >60 year legacy of baclofen by walking through the history, pharmacology, synthesis, drug metabolism, routes of administration, and societal impact of this Classic in chemical neuroscience.

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“…To date, a considerable number of α,α-difluoromethyl ketones (DFMKs) have been prepared and evaluated mostly as protease inhibitors ( Figure 1 ). Non-peptidic DFMKs 1 and 2 have been proposed as reversible covalent inhibitors of the Anopheles gambiae acetylcholinesterase ( Ag AChE) [ 23 ], whereas compound 3 was investigated as an agonist of the γ-aminobutyric acid type B (GABA B ) receptor [ 24 ]. Compounds 4 and 5 are the only two examples of peptidic DFMKs reported in the literature so far [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses

Citarella

Gentile

Rescifina

et al. 2021

IJMS

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The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.

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Agonists of the γ-aminobutyric acid type B (GABAB) receptor derived from β-hydroxy and β-amino difluoromethyl ketones

Cited by 7 publications

References 27 publications

The GABAB Receptor—Structure, Ligand Binding and Drug Development

The GABAB Receptor—Structure, Ligand Binding and Drug Development

Classics in Chemical Neuroscience: Baclofen

Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses

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