Γ-aminobutyric Acid Analogues Research Articles

Synthesis of R-GABA Derivatives via Pd(II) Catalyzed Enantioselective C(sp3)-H Arylation and Virtual Validation with GABAB1 Receptor for Potential leads.

GABA (γ-amino butyric acid) analogues like baclofen, tolibut, phenibut, etc., are well-known GABAB1 inhibitors and pharmaceutically important drugs. However, there is a huge demand for more chiral GABA aryl analogues with promising pharmacological actions. Here, we demonstrate the chiral ligand acetyl-protected amino quinoline (APAQ) mediated enantioselective synthesis of GABAB1 inhibitor drug scaffolds from easily accessible GABA via Pd-catalyzed C(sp3)-H activation. The synthetic methodology shows moderate to good yields, up to 74% of ee. We have successfully demonstrated the deprotection and removal of the directing group to synthesize R-tolibut in 86% yield. Further, we employed computation to probe the binding of R-GABA analogues to the extracellular domain of the human GABAB1 receptor. Our Rosetta-based molecular docking calculations show better binding for four R-enantiomers of GABA analogues than R-baclofen and R-phenibut. In addition, we employed GROMACS MD simulations and MMPB(GB)SA calculations to identify per-residue contribution to binding free energy. Our computational results suggest analogues (3R)-4-amino-3-(3,4-dimethylphenyl) butanoic acid, (3R)-4-amino-3-(3-fluorophenyl) butanoic acid, (3R)-3-(4-acetylphenyl)-4-aminobutanoic acid, (3R)-4-amino-3-(4-methoxyphenyl) butanoic acid, and (3R)-4-amino-3-phenylbutanoic acid are potential leads which could be synthesized from our methodology reported here.

Comprehensive study of metabolic changes induced by a ketogenic diet therapy using GC/MS- and LC/MS-based metabolomics

ObjectiveThe ketogenic diet (KD), a high-fat and low-carbohydrate diet, is effective for a subset of patients with drug-resistant epilepsy, although the mechanisms of the KD have not been fully elucidated. The aims of this observational study were to investigate comprehensive short-term metabolic changes induced by the KD and to explore candidate metabolites or pathways for potential new therapeutic targets. MethodsSubjects included patients with intractable epilepsy who had undergone the KD therapy (the medium-chain triglyceride [MCT] KD or the modified Atkins diet using MCT oil). Plasma and urine samples were obtained before and at 2–4 weeks after initiation of the KD. Targeted metabolome analyses of these samples were performed using gas chromatography-tandem mass spectrometry (GC/MS/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). ResultsSamples from 10 and 11 patients were analysed using GC/MS/MS and LC/MS/MS, respectively. The KD increased ketone bodies, various fatty acids, lipids, and their conjugates. In addition, levels of metabolites located upstream of acetyl-CoA and propionyl-CoA, including catabolites of branched-chain amino acids and structural analogues of γ-aminobutyric acid and lactic acid, were elevated. ConclusionsThe metabolites that were significantly changed after the initiation of the KD and related metabolites may be candidates for further studies for neuronal actions to develop new anti-seizure medications.

Enantioselective Giese Additions of Prochiral α-Amino Radicals.

Amines featuring an adjacent stereocenter are important building blocks, and recent years have seen remarkable growth in methods forming these via prochiral α-amino radical intermediates. However, very few can exert control over the newly formed stereocenter. We disclose a strategy to overcome this in the context of one of the most widely used radical carbon-carbon bond forming reactions, the Giese reaction. Incorporation of a removable basic heteroarene into the substrate enables a network of attractive noncovalent interactions between a phosphoric acid catalyst, the subsequently formed α-amino radical, and the Giese acceptor, allowing the catalyst to exert control during the C-C bond forming step. Deprotection of the products leads to analogues of γ-aminobutyric acid. We anticipate that this strategy will be applicable to other asymmetric radical transformations in which catalyst control is presently challenging.

Synthesis of γ-Aminobutyric Acid (GABA) Analogues Conformationally Restricted by Bicyclo[3.1.0]hexane/hexene or [4.1.0]Heptane/heptene Backbones as Potent Betaine/GABA Transporter Inhibitors.

Novel γ-aminobutyric acid (GABA) analogues 3-5, having a bicyclo[3.1.0]hexene, [4.1.0]heptane, or [4.1.0]heptene backbone, respectively, were designed from the bioactive form analysis of the previous inhibitor 2 with a bicyclo[3.1.0]hexane backbone. Compounds 3-5 and 2 were synthesized from a common 1,7-diene intermediate 6 using ring-closing metathesis (RCM) to construct the key bicyclo backbones. Compounds 3-5 strongly inhibit betaine/GABA transporter 1 (BGT1) uptake, but compound 4 stands out with its selective low micromolar potency.

Analytical quality by design-based LC-MS/MS method for the determination of Riociguat in its formulations

A Novel UPLC–MS/MS Method for Determination of γ-Amino Butyric acid Analogue in Human Plasma: Application to Pharmacokinetic StudyAnju Aji, Sarita Karthikeyan, Sarabjit Singh, Shivanand P. Puthli

Organocatalytic Asymmetric Michael Addition in Aqueous Media by a Hydrogen-Bonding Catalyst and Application for Inhibitors of GABAB Receptor

Catalysts based on (R, R)-1,2-diphenylethylenediamine are, as chiral organic catalysts, applied to the asymmetric Michael addition to α, β-unsaturated nitroalkenes under neutral conditions. The role of an aqueous medium for organic catalytic activity can be reversed concerning hydrophilic-hydrophobic function depending on the reaction conditions. In this study, to provide an environmentally friendly system, the thiourea-based catalyst substituted with 3,5-(CF3)2-Ph was used in water solvents. The hydrophobic effect of the substituent provided fast reaction, high chemical yield, and mirror-image selectivity. This reaction allowed the preparation of GABAB agonists in an optically pure manner. Additionally, GABA (γ-aminobutyric acid) analogs such as baclofen and phenibut were synthesized as R-type S-type with high optical purity.

Lesser Known Uses of γ-Aminobutyric Acid Analogue Medications in Otolaryngology.

In otolaryngology, γ-aminobutyric acid (GABA) analogues have been previously analyzed for their roles in neuropathic pain, chronic cough, tinnitus, and perioperative analgesia. The primary aim of this study is to comprehensively summarize and synthesize the existing evidence for lesser known uses of gabapentin and pregabalin in otolaryngology. A scoping review conducted of the available English-language literature was performed by two authors through April 1, 2021. The Preferred Reporting Items for Systematic Review and Meta-Analysis criteria were followed, and a quality assessment of included studies was performed using the Methodological Index for Non-Randomized Studies. Ten studies met inclusion criteria. Three studies found that gabapentin may reduce gastrostomy tube usage and improve swallowing function in head and neck cancer patients undergoing radiation therapy (RT). Three studies suggested that gabapentin may help reduce opiate use when used as a primary analgesic in patients with radiation-induced mucositis. One study demonstrated that pregabalin-reduced trismus severity in patients with radiotherapy-induced trismus. One study demonstrated gabapentin may be useful in patients with phonasthenia. Two studies demonstrated that GABA analogues may be a useful adjunct in patients with globus pharyngeus in the context of likely laryngeal sensory neuropathy. The most promising potential uses for GABA analogues identified in this review are for improving swallowing, trismus, and narcotic overuse after RT. The benefit of GABA analogues for improving nonorganic voice disorders is also promising while the benefit for globus pharyngeus when possibly related to laryngeal sensory neuropathy is inconclusive. Laryngoscope, 132:954-964, 2022.

A Review on Different Analytical Techniques for Determination of DNP Drugs and their Metabolites in Pharmaceutical Formulations

Background: Neuropathy is the most common perplexity of diabetes type 1 and 2. About 50% of diabetic patients develop diabetic neuropathic pain (DNP). At the beginning of diabetic neuropathy, there is a loss of sense, especially in the lower limb, accompanied by pain, and difficulty in movement. Glucose regulation effectively prevents the development of diabetic neuropathy in type 1 diabetic patients, but the consequences in type 2 diabetic patients are more drastic. Introduction: No single treatment exists to prevent or renovate the pain caused by diabetic neuropathy. The drugs used for the treatment of DNP come in various formulations and with different storage conditions. To date, a number of analytical methodologies have been reported for the analysis of DNP drugs. Few reports are published describing analytical methods of single DNP drugs. Methods: The main objective of this review is to compile the different analytical methods developed at UV-Vis (Ultraviolet-visible) spectrophotometer, HPLC (High Performance Liquid Chromatography), and LC-MS (Liquid Chromatography-Mass spectrometry) to identify and quantify the drug content in various formulations, which are used to treat or prevent the diabetic neuropathic pain mainly focusing on γ-aminobutyric acid analogues, anti-depressants, Serotonin Noradrenaline Reuptake Inhibitors (SNRIs), aldose reductase inhibitors, opioids, and dietary supplements. Results and Discussion: We have compiled UV-Vis, HPLC, and Liquid Chromatography-Mass spectrometry analytical methods developed to study the pharmacokinetic profile, quantify drug content, and their metabolites in plasma as well as pharmaceutical formulations. Conclusion: The authors believe that the mentioned studies in the report will help audible readers to select a suitable method for analysis of these drugs and also help researchers to develop a more convenient, fast, and sensitive method for these.

The preparative synthetic approach to α,α-difluoro-γ-aminobutyric acid

Aim . To develop a convenient synthetic approach for the preparation of multigram amounts of 2,2-difluoro-γ-aminobutyric acid, which is pharmacologically promising analog of γ-aminobutyric acid (GABA). Results and discussion . α,α-Difluoro-γ-aminobutyric acid (2,2-difluoro-GABA, 53 g) has been synthesized using the reaction of ethyl bromodifluoroacetate (EBDFA) addition to benzyl acrylate in the presence of copper as a key stage. Experimental part . The reaction of EBDFA with benzyl acrylate in the presence of copper and tetramethylethylenediamine (TMEDA) was carried out; the resulting product was transformed to the target α,α-difluoro-γ-aminobutyric acid (in the form of hydrochloride) by consecutive debenzylation, Curtius rearrangement and treatment with hydrochloric acid to remove protecting groups. The synthesis was scaled up for the preparation of 53 g of α,α-difluoro-γ-aminobutyric acid. The ethyl ester of α,α-difluoro-γ-aminobutyric acid was also prepared and further transformed to 3,3-difluoropyrrolidine-2-one. The structure of the compounds synthesized was confirmed by 1 Н, 13 C and 19 F NMR spectroscopy, mass spectrometry and elemental analysis. Conclusions . It has been shown that the synthetic approach developed can be used for the preparation of α,α-difluoro-γ-aminobutyric acid in multigram amounts. The pathway is much more convenient, cheaper and safer compared to the method earlier described. Received: 30.07.2020 Revised: 19.08.2020 Accepted: 27.08.2020

Pharmacokinetic Profiles of Gabapentin after Oral and Subcutaneous Administration in Black-tailed Prairie Dogs (Cynomys ludovicianus).

In veterinary and human medicine, gabapentin (a chemical analog of γ-aminobutyric acid) is commonly prescribed to treat postoperative and chronic neuropathic pain. This study explored the pharmacokinetics of oral and subcutaneous administration of gabapentin at high (80 mg/kg) and low (30 mg/kg) doses as a potential analgesic in black-tailed prairie dogs (Cynomys ludovicianus; n = 24). The doses (30 and 80 mg/kg) and half maximal effective concentration (1.4 to 16.7 ng/mL) for this study were extrapolated from pharmacokinetic efficacy studies in rats, rabbits, and cats. Gabapentin in plasma was measured by using an immunoassay, and data were evaluated using noncompartmental analysis. The peak plasma concentrations (mean ±1 SD) were 42.6 ±14.8 and 115.5 ±15.2 ng/mL, respectively, after 30 and 80 mg/kg SC and 14.5 ±3.5 and 20.7 ±6.1 ng/mL after the low and high oral dosages, respectively. All peak plasma concentrations of gabapentin occurred within 5 h of administration. Disappearance half-lives for the low and high oral doses were 7.4 ± 6.0 h and 5.0 ± 0.8 h, respectively. The results of this study demonstrate that oral administration of gabapentin at low (30 mg/kg) doses likely would achieve and maintain plasma concentrations at half maximum effective concentration for 12 h, making it a viable option for an every 12-h treatment.

A Remarkable Difference That One Fluorine Atom Confers on the Mechanisms of Inactivation of Human Ornithine Aminotransferase by Two Cyclohexene Analogues of γ-Aminobutyric Acid.

Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate-dependent enzyme, plays a critical role in the progression of hepatocellular carcinoma (HCC). Pharmacological selective inhibition of hOAT has been shown to be a potential therapeutic approach for HCC. Inspired by the discovery of the nonselective aminotransferase inactivator (1R,3S,4S)-3-amino-4-fluoro cyclopentane-1-carboxylic acid (1), in this work, we rationally designed, synthesized, and evaluated a novel series of fluorine-substituted cyclohexene analogues, thereby identifying 8 and 9 as novel selective hOAT time-dependent inhibitors. Intact protein mass spectrometry and protein crystallography demonstrated 8 and 9 as covalent inhibitors of hOAT, which exhibit two distinct inactivation mechanisms resulting from the difference of a single fluorine atom. Interestingly, they share a similar turnover mechanism, according to the mass spectrometry-based analysis of metabolites and fluoride ion release experiments. Molecular dynamics (MD) simulations and electrostatic potential (ESP) charge calculations were conducted, which elucidated the significant influence of the one-fluorine difference on the corresponding intermediates, leading to two totally different inactivation pathways. The novel addition-aromatization inactivation mechanism for 9 contributes to its significantly enhanced potency, along with excellent selectivity over other aminotransferases.

Access to Chiral GABA Analogues Bearing a Trifluoromethylated All-Carbon Quaternary Stereogenic Center through Water-Promoted Organocatalytic Michael Reactions.

Water enables the highly challenging enantioselective Michael addition of sterically congested β-trifluoromethyl-β-aryl- or -alkyl-substituted nitroolefins with dithiomalonates. Under on-water conditions, the reaction rates were remarkably accelerated as a result of enforced hydrophobic interactions between catalysts and reactants. Takemoto-type thiourea catalysts are very effective for this transformation, affording highly enantioenriched Michael adducts that provide simple access to chiral γ-aminobutyric acid (GABA) analogues with a β-trifluoromethylated quaternary stereocenter.

Construction of 4-substituted 2-(pyrrolidine-3-yl)acetic acid derivatives as cyclic γ-aminobutyric acid analogues employing intermolecular [2+2]-photocycloaddition as key steps

The synthesis of new 2-(pyrrolidine-3-yl)acetic acid derivatives as cyclic γ-aminobutyric acid analogues, which are additionally substituted at the 4-position, is reported. A de Mayo reaction, i.e. a combination of an intermolecular [2+2]-photocycloaddition of 1,3-dioxinones with N-protected 3-pyrroline and a fragmentation reaction of the resulting cyclobutane moiety, represent the key steps.

Effect of gabapentin on sleep patterns disturbed by epilepsy

For a long time, numerous sleep alterations induced by nocturnal epilepsy have been described. Such alterations include sleep fragmentation, decrement of sleep efficiency, increment of the wake time after sleep onset (WASO), increment of light sleep, and decrement of sleep depth. On the other hand, gabapentin (GBP), an antiepileptic drug analog of γ-aminobutyric acid (GABA) used as adjunctive and eventually, as a monotherapeutic treatment, induces a significant improvement in patients with both focal and secondarily generalized partial seizures. In experimental epilepsy models, this drug protects against pentylenetetrazol (PTZ)-induced convulsions. In consideration of such GBP properties, the aim of this work was to investigate its efficacy to protect against sleep disturbances provoked by convulsive seizures induced by the administration of PTZ.Nine-hour (9-hour) polygraphic studies were carried out in chronically implanted male adult Wistar rats separated into 4 different groups of 6 individuals. Control recordings in each group were done after saline administration. One group received a SC Subcutaneous (SC) injection of 50 mg/kg of PTZ alone while the other three groups were injected with either 15, 30, or 60 mg/kg IP Intraperitoneal (IP) of GBP 30 min prior to PTZ (50 mg/kg SC) administration.Animals displayed the whole range of electrophysiological and behavioral manifestations of the disease during the epileptic episodes induced by PTZ administration, and the states of vigilance were significantly altered. Insomnia occurred immediately after PTZ injection preceding the appearance of the first epileptic symptoms. Thus, both slow wave sleep (SWS) and rapid eye movement sleep (REM sleep) were completely inhibited during a relatively long period of time.The disturbing effects of epilepsy on sleep decreased when animals were under GBP treatment. Improvement of sleep was dependent on the administered dose of this antiepileptic drug.

Tricyclic Antidepressant and/or γ-Aminobutyric Acid-Analog Use Is Associated With Fall Risk in Diabetic Peripheral Neuropathy.

Peripheral neuropathy is a common diabetes complication that can increase fall risk. Regarding fall risk, the impact of pain management using tricyclic antidepressants (TCAs) or γ-aminobutyric acid (GABA) analogs is unclear because these medications can also cause falls. This study investigates the impact of these drugs on fall and fracture risk in older diabetic peripheral neuropathy (DPN) patients. Historical cohort study with 1-to-1 propensity matching of TCA/GABA-analog users and nonusers. Nationally representative 5% Medicare sample between the years 2008 and 2010. After applying all selection criteria, 5,550 patients with prescription and 22,200 patients without prescription of TCAs/GABA-analogs were identified. Both patient groups were then stratified for fall history and matched based on propensity of receiving TCAs/GABA-analogs within each group. Patients were followed until the first incidence of fall or the first incidence of fracture during the follow-up period (for up to 5 years). After matching, users and nonusers were largely similar. After covariate adjustment, TCA/GABA-analog use was associated with a statistically significant increase in fall risk (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 1.03-1.20), but was not associated with fracture risk (adjusted HR = 1.09; 95% CI = 0.99-1.19) in the conventional analysis. Treating TCA/GABA-analog use as a time-dependent covariate resulted in statistically significant associations of TCA/GABA-analog use with both fall and fracture risk (HR = 1.26 [95% CI = 1.17-1.36]; and HR = 1.12 [95% CI = 1.02-1.24], respectively). Among older patients with DPN, GABA-analogs or TCAs increase fall risk and possibly fracture risk. Use of these medications is therefore a potentially modifiable risk factor for falls and fractures in this population.

Enantioselective Synthesis of Pharmaceutically Active γ-Aminobutyric Acids Using a Tailor-Made Artificial Michaelase in One-Pot Cascade Reactions.

Chiral γ-aminobutyric acid (GABA) analogues represent abundantly prescribed drugs, which are broadly applied as anticonvulsants, as antidepressants, and for the treatment of neuropathic pain. Here we report a one-pot two-step biocatalytic cascade route for synthesis of the pharmaceutically relevant enantiomers of γ-nitrobutyric acids, starting from simple precursors (acetaldehyde and nitroalkenes), using a tailor-made highly enantioselective artificial “Michaelase” (4-oxalocrotonate tautomerase mutant L8Y/M45Y/F50A), an aldehyde dehydrogenase with a broad non-natural substrate scope, and a cofactor recycling system. We also report a three-step chemoenzymatic cascade route for the efficient chemical reduction of enzymatically prepared γ-nitrobutyric acids into GABA analogues in one pot, achieving high enantiopurity (e.r. up to 99:1) and high overall yields (up to 70%). This chemoenzymatic methodology offers a step-economic alternative route to important pharmaceutically active GABA analogues, and highlights the exciting opportunities available for combining chemocatalysts, natural enzymes, and designed artificial biocatalysts in multistep syntheses.

New salicylic acid and pyroglutamic acid conjugated derivatives confer protection to bread wheat against Zymoseptoria tritici.

To promote sustainable agriculture and healthy food, research that contributes towards a new generation of eco-friendly phytosanitary compounds is increasingly encouraged. The plant hormone salicylic acid (SA) is known for its ability to induce resistance in plants against a wide range of pathogens, whereas pyroglutamic acid (PGA), a constrained analogue of γ-aminobutyric acid, has never been studied in the context of plant protection. The present study investigated for the first time the protection efficacy of SA and PGA and five new conjugated derivatives against Zymoseptoria tritici, the main pathogen in wheat crops. SA and four derivatives showed significant disease severity reductions in planta (up to 49%). In vitro assays revealed that some molecules, including SA, displayed a small direct antifungal activity, whereas others, such as PGA, showed no effect. This finding suggests that, especially for molecules without any direct activity, the mode of action relies mainly on the induction of plant resistance. Further investigations are needed to identify the defence pathways involved in plant resistance mechanisms elicited or primed by the molecules. The manufacture of these products was easily achieved on a scale of tens of grams of raw materials, and is easily scalable. The synthetic pathway is simple, short and inexpensive. For all of these reasons, the production of the target molecules is attractive for producers, whereas the prospect of a generation of non-polluting compounds with lasting efficiency against Z. tritici in wheat comes at a key moment for the sustainability of agriculture. © 2018 Society of Chemical Industry.

A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine scaffold.

An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid-a bicyclic conformationally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of 2,3-bis(chloromethyl)pyridine and a C1-binucleophile and the catalytic reduction of the pyridine ring as the key steps and allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]pyridine scaffold geometry showed that this template can be considered truly three-dimensional.

Design and synthesis of cyclopropane-based conformationally restricted GABA analogues as selective inhibitors for betaine/GABA transporter 1

We previously designed and synthesized a series of cyclopropane-based conformationally restricted analogues of γ-aminobutyric acid (GABA). The study demonstrated that the critical conformation of the analogues that selectively active to betaine/GABA transporter 1 (BGT1) subtype is the trans-syn-form, in which the amino and carboxyl groups are in trans-configuration and the cyclopropane ring and the carboxyl group are in syn-arrangement. In this study, we designed and synthesized cyclopropane-based GABA analogues, which were conformationally restricted in the trans-syn-form by cyclopropylic strain based on the stereochemistry of the carbon adjacent to cyclopropane. Their conformation was confirmed as the syn-form by calculations and NMR studies, and their pharmacological evaluation clarified that compounds 11a and 11d had the BGT1 selectivity, although their inhibitory effects were insufficient.

Synthesis of β-Substituted γ-Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis.

β-Substituted chiral γ-aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β-substituted γ-aminobutyric acid derivatives through visible-light-induced photocatalyst-free asymmetric radical conjugate additions is reported. Various β-substituted γ-aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42-89 %) and with excellent enantioselectivity (90-97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)-pregabalin, (R)-baclofen, (R)-rolipram, and (S)-nebracetam.