GABA Analogues Research Articles

1,5-Disubstituted-1,2,3-Triazoles as GABA analogues: Synthesis, QSAR and biological evaluation as Pseudomonas fluorescens GABA-AT inhibitors

We report the synthesis of a new series of γ-aminobutyric acid (GABA) analogues as possible GABA-AT inhibitors, where the nitrogen at the Ƴ-position is contained in a 1,5-disubstituted-1,2,3-triazole ring system. The triazole ring system was assembled by the Ru(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (RuACC) protocol. GABA-AT inhibition activity was predicted by means of a QSAR model that was constructed in this work. Different molecular descriptors families were employed for its construction, like steric type (Wap and PW5), solubility type (ΔPSA), and electronic type (ΔTriazole3). Additionally, a similarity analysis based on the electronic profile of 1,5-triazole and 1,4-triazole GABA analogues was done to support the QSAR predictions. Finally, the three best candidates were biologically tested as Pseudomonas fluorescens GABA-AT inhibitors showing an inhibition percent compared to FDA approved inhibitors.

Gabapentin-Induced Adrenal Insufficiency: The Hypothalamic-Pituitary-Adrenal Axis Stress Misresponse and Risk of Infection: A Case Report and Literature Review.

This literature review, in light of the presented case report, explores the complex interplay between gabapentin (GBP), a gamma-aminobutyric acid (GABA) analog, and the hypothalamic-pituitary-adrenal (HPA) axis in patients undergoing major surgical procedures. It specifically investigates the potential impact of GBP on cortisol levels, stress responses, and infection risk, illustrated by a detailed clinical case. This review combines a comprehensive literature search with a case report of a 17-year-old male with osteosarcoma who experienced transient adrenal insufficiency and infections while receiving GBP. The case is analyzed in the context of the existing literature on GBP and the HPA axis. The findings highlight the intricate relationship between GBP use, adrenal insufficiency, and infection susceptibility. It underscores the need for further research and clinical vigilance when prescribing GBP to patients with underlying medical conditions, particularly in the context of major surgical procedures. The review underscores the need for further research and clinical vigilance when prescribing GBP, particularly in perioperative settings. In conclusion, GBP's effects on the HPA axis and immune responses are complex and multifaceted. Clinicians should exercise caution when prescribing GBP, especially for patients with underlying conditions undergoing major surgery. Further research is needed to elucidate the mechanisms of GBP's influence on cortisol levels and stress responses.

Drug Intoxication Associated with Pregabalin: An Autopsy Case

Pregabalin is a gamma-aminobutyric acid analogue; it has been used clinically as an anticonvulsant and analgesic agent. Few documented reports exist of deaths resulting from pregabalin overdose. This report discusses a case of pregabalin intoxication in a 27-year-old male, who was found unconscious in a prison and later pronounced dead at a local hospital. An autopsy and toxicological analysis revealed the presence of pregabalin, alprazolam, diazepam, escitalopram, fluoxetine, lorazepam, bromazepam, flunitrazepam, zolpidem, and piroxicam. The concentrations of pregabalin and alprazolam were 10.3 mg/L and 0.10 mg/L in heart blood, and 11.4 mg/L and 0.08 mg/L in femoral blood, respectively. The other detected drugs were within therapeutic concentrations. Ethyl alcohol was not detected in the blood. Although the pregabalin concentration was within the therapeutic or toxic range, the concomitant use of other drugs, particularly benzodiazepines and zolpidem, likely enhanced its toxicity. Based on the autopsy findings and toxicological results, the cause of death was determined to be multidrug intoxication, including pregabalin. Although pregabalin is generally considered safe and deaths from its use alone are very rare, it can be fatal at relatively low blood concentrations when combined with opioids or other medications. The rising use of pregabalin in Korea increases the risk of overdose deaths, similar to this case. Therefore, in forensic practice, the possibility of such fatalities should be considered when pregabalin is detected.

GABA Analogue HSK16149 in Chinese Patients With Diabetic Peripheral Neuropathic Pain

Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China. To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP. This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose. In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment. The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences. Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common. Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated. ClinicalTrials.gov Identifier: NCT04647773.

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

Synthesis and physicochemical evaluation of tetrafluorinated GABA analogue

Synthesis of 2,2,3,3-tetraftluoro-γ-aminobutyric acid (tetraF-GABA) starting from commercially available 2,2,3,3-tetrafluorobutane-1,4-diol is described. The straightforward nine-step reaction sequence allowed the production of up to 20 g of the target amino acid in 41 % overall yield. Potentiometric titration revealed increased acidity of both ionizable moieties in the title compound (the pKa values were diminished by 1.6 and 4.0 units for the COOH and NH3+ groups, respectively, as compared to parent GABA). X-ray diffraction studies and DFT calculations demonstrated different preferential conformations in solid state and solution, although the fluorine gauche effect was observed in both cases.

Photodecarboxylative Ring Annulation of α‐ and β‐Functionalized Phthaloyl‐GABA Derivatives: Bioactive Pyrroloisoindolinones with High Quantum Efficiency

AbstractThe triplet‐sensitized (by the solvent acetone) as well as the direct (λex=300–320 nm) photochemical decarboxylation of N‐phthaloylated γ‐aminobutyric acid (GABA) derivatives are versatile and high‐yielding routes to benzopyrrolizidines via intramolecular electron transfer initiated decarboxylation followed by radical coupling. The ß‐mono‐ and ß,ß'‐disubstituted N‐phthaloyl GABA derivatives 7 a–7 g, respectively, were applied as substrates. Decarboxylative photocyclization yielded hydroxy benzopyrrolizidines 8 a–8 g in high chemical yields and with moderate diastereoselectivities from the ß‐monosubstituted substrates. The analogous α‐substituted GABA derivatives 11 a–11 c were also applied as potential substrates for memory of chirality effects. The reaction quantum yields of the photodecarboxylation reactions for the parent GABA derivative 13 and for the new substrates 7 h and 11 a were determined by the quantum yield determination system (QYDS) and showed a remarkable concentration dependency indicating aggregation at higher substrate concentrations. Inhibition studies on the atherogenic human serine hydrolase cholesterol esterase showed derivatives 8 a and 8 d to exhibit a hyperbolic mode of inhibition with moderate IC50 values of about 60–80 μM.

Predictive Factors for 30-Day Readmission and Increased Healthcare Utilization in Sickle Cell Disease Patients: A Single-Center Comparative Retrospective Study.

SCD poses a significant healthcare burden. Understanding the factors contributing to high healthcare utilization and readmissions is crucial for improving the quality of care provided. This retrospective comparative observational study was conducted at King Saud University Medical City and included 160 SCD patients. A comparison was made between patients with no readmission and patients with at least one 30-day readmission. Another comparison was done between high healthcare-utilizing patients and low healthcare-utilizing patients. A regression model for 30-day readmission prediction was created. Readmission was significantly higher in patients using opioids, following up with pain clinics, and having a history of AVN (p= 0.002, p=0.028 and p=0.025 respectively). Higher healthcare utilization was associated with older age, smoking, use of opioids and GABA analogs, and psychiatric illnesses, including depression, substance use disorder, and anxiety. Predictors of 30-day readmission were hydroxyurea use (odds ratio, 2.819 [95% CI,1.082 to 7.34], p = 0.034), follow-up with pain management clinics (odds ratio, 2.248 [95% CI,1.547 to 3.266], p = 0.001), and SCD genotype (SS genotype) (odds ratio, 1.754 [95% CI,1.012 to 3.042], p = 0.045). Using the Paracetamol/Codeine combination significantly reduced the likelihood of readmission within 30 days of discharge. This study identified factors associated with 30-day readmission rate and high healthcare utilization among SCD patients. Strategies to reduce readmissions may include specialized SCD clinics, educational programs for patients, improved physician awareness of mental health screening, and further research on the impact of opioid use. Limitations include retrospective nature, single-center design, reliance on self-reported data, and exclusion of critically ill patients. However, despite the limitations, this study could lay a foundation for future projects aiming to optimize care and outcomes for patients living with SCD.

Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant to treat partial seizures and neuropathic pain. While a majority of the side effects are associated with the nervous system, emerging evidence suggests a high risk for heart disease in the patients taking GBP. Given GBP can bind with high affnity to the α2δ subunits of voltage-gated Ca2+ channels (VGCCs) to block Ca2+ influx of cardiomyocytes, we hypothesize GBP suppresses cardiac function by evoking calcium signaling dysfunction. By using a preclinical rat model treated with GBP, we investigated (1) the acute cardiovascular responses to GBP (bolus i.v. injection; 50 mg/kg, 100 mg/ml x 0.1 ml in 3 min) and (2) the effects of chronic GBP treatment (i.p. 100 mg/kg/day x 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane-anesthesia, blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics of the rats were measured using two Millar pressure transducers; one was implanted in abdominal aorta via right femoral artery, and the another was implanted in the LV chamber via right carotid artery. The LV myocardium was analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction, with the brain cortex used as a control tissue. In experiment (1), we found that i.v. GBP treatment significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (*p &lt; 0.05 and **p &lt; 0.01 vs baseline; n = 4/group). This cardiovascular inhibition started at the injection time point and lasted at least 60 min, with a maximal effect appearing at 30 min post injection. In experiment (2), we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium of these rats, we used mass spectra to identify 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Particularly, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain, suggesting a myocardium-specific dysregulation of calcium signaling pathway, which may play a critical role in GBP-induced cardiac inhibition. Subsequent bioinformatics assays revealed a reduced Ca2+ release of sarcoplasmic reticulum (SR) and increased electrophoretic Ca2+ uptake into the matrix of mitochondria in the hearts of GBP-treated rats. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes where GBP binds to VGCCs to reduce extracellular Ca2+ influx and cytosolic Ca2+ release from SR, resulting in blockage of excitation-contraction coupling. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function. This project is funded by NIH R01 HL 160820. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Appropriate use of medication among home care adult cancer patients at end of life: a retrospective observational study

BackgroundMedications are commonly used for symptom control in cancer patients at the end of life. This study aimed to evaluate medication utilization among home care palliative patients with cancer at the end of life and assess the appropriateness of these medications.MethodThis retrospective observational study included adult cancer patients who received home care in 2020. Medications taken during the last month of the patient’s life were reviewed and classified into three major categories: potentially avoidable, defined as medications that usually have no place at the end of life because the time to benefit is shorter than life expectancy; medications of uncertain appropriateness, defined as medications that need case-by-case evaluation because they could have a role at the end of life; and potentially appropriate, defined as medications that provide symptomatic relief.ResultsIn our study, we enrolled 353 patients, and 2707 medications were analyzed for appropriateness. Among those, 1712 (63.2%) were classified as potentially appropriate, 755 (27.9%) as potentially avoidable, and 240 (8.9%) as medications with uncertain appropriateness. The most common potentially avoidable medications were medications for peptic ulcers and gastroesophageal reflux disease (30.5%), vitamins (14.6%), beta-blockers (9.8%), anticoagulants (7.9%), oral antidiabetics (5.4%) and insulin products (5.3%). Among the potentially appropriate medications, opioid analgesics were the most frequently utilized medications (19.5%), followed by laxatives (19%), nonopioid analgesics (14.4%), gamma-aminobutyric acid analog analgesics (7.7%) and systemic corticosteroids (6%).ConclusionIn home care cancer patients, approximately one-third of prescribed medications were considered potentially avoidable. Future measures to optimize medication use in this patient population are essential.

A case of delirium following treatment with low dose mirtazapine and pregabalin

IntroductionPregabalin is a gamma-aminobutyric acid analogue used for the treatment of neuropathic pain, partial-onset-seizures, fibromyalgia, and anxiety disorders. Mirtazapine is an atypical antidepressant used in major depression and often prescribed off-label for insomnia. Delirium, an acute confusional state, is a very rare adverse reaction of both medications.ObjectivesWe report a case of an elderly patient treated with low dose pregabalin and mirtazapine who developed drug-induced delirium which resolved rapidly upon withdrawal of both drugsMethods A 75-year-old woman was admitted for symptoms of anxiety, various bodily complaints (dysphagia, headache, tinnitus, weakness) and sleep-onset insomnia over the preceding 2 months. On admission, examination revealed an apparently anxious, uneasy and emotional looking patient. Mini mental state examination, as well as clock drawing and copying were normal, suggesting absence of cognitive impairment. Physical examination was unrevealing except for high blood pressure recordings (150/90 mmHg). Laboratory testing indicated creatinine at 1.19 mg/dl, with a creatinine clearance moderately decreased at 38 ml/min. Upon admission, she was placed on pregabalin 25 mg bid and mirtazapine 30 mg ¼ tablet qd.ResultsThree days after admission, pregabalin was increased to 25 mg tid. On the same day and about 2 hours after the night dose, the patient acutely developed delirium: she presented confusion, disorientation, incoherence, restlessness and deterioration of her anxiety. On physical examination she was afebrile with no hypertonia or ataxia. An urgent brain magnetic resonance imaging was grossly unrevealing. Pregabalin and mirtazapine were discontinued, as a drug-induced delirium was suspected. She received as a symptomatic treatment lorazepam progressively up to 4 mg qd. Symptoms of delirium resolved rapidly, and she was discharged days later with full functional recoveryConclusionsCases of delirium have been described following treatment with pregabalin, but in significantly higher doses. Pregabalin relies heavily on renal clearance for its excretion and the dose should be adjusted in patients with creatine clearance below 60 ml/min. As our patient had a moderate decrease in renal clearance, we prescribed a dose within suggested limits, but in combination with mirtazapine led to the appearance of a drug-induced delirium. In conclusion, combined therapy with low-dose pregabalin and mirtazapine seems to account for the development of delirium in our patient as based on its temporal association with the initiation of this drug combination and its prompt resolution upon withdrawal of these two agentsDisclosure of InterestNone Declared

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.

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro-nutraceuticals.

Arising out of a PhD project more than 50 years ago to synthesise analogues of the neurotransmitter GABA, a series of new chemical entities were found to have selective actions on ionotropic GABA receptors. Several of these neurochemicals are now commercially available. A new subtype of these receptors was discovered that could be a target for the treatment of myopia, the facilitation of learning and memory, and the improvement of post-stroke motor recovery. The development of these new chemical entities over many years demonstrates the importance of neurochemicals with which to investigate selective aspects of GABA receptors and illustrates the significance of collaboration between chemists and biologists in neurochemistry. Vital were the improvements in synthetic organic chemistry and the use of functional human receptors expressed in oocytes. Current interest in ionotropic GABA receptors includes the clinical development of subtype-specific agents and the role of gain-of-function receptor variants in epilepsy. Dietary flavonoids were found to cross the blood-brain barrier to influence brain function. Natural and synthetic flavonoids had a range of effects on GABA receptors, ranging from positive, silent, and negative allosteric modulators, to even second-order modulation of first-order modulators. Flavonoids have been called "a new family of benzodiazepines." Like benzodiazepines, flavonoids reduce stress. Stress produces changes in GABA receptors in the brain that may be because of changes in endogenous modulators, such as neurosteroids and corticosteroids. GABA also occurs naturally in the diet leading to studies of the effects of oral GABA on brain function. This finding has resulted in studies of GABA and related neurochemicals as neuro-nutraceuticals. GABA systems in the gut microbiome are essential to such studies. The actions of oral GABA and of GABA-enriched beverages and foodstuffs are now an area of considerable scientific and commercial interest. GABA is a deceptively simple chemical that can take up many shapes, which may underlie its complex functions. The need for new chemical entities with selective actions for further studies highlights the need for continuing collaboration between chemists and biologists.

Features of Klotho Protein Expression in Rat Kidneys in Experimental Hyperglycemia Against the Background of Pharmacological Correction with GABA Derivatives

The aim is to identify the features of Klotho protein expression in the epithelium of the convoluted tubules of the kidney during prolonged experimental hyperglycemia and pharmacological correction with GABA derivatives. Material and methods. The study used 50 mongrel male rats (initial weight: 330,0–360,0 g) with streptozotocin diabetes lasting 6 months. 6 months after the injection of streptozotocin (60 mg/kg), animals with a glycemic level of ≥ 15 mmol/l were included in the study (after 4 hours of food deprivation), then GABA derivatives (aminalon, mefargine, succicard) were administered orally for 30 days. Proteinuria and serum creatinine concentrations were evaluated. After euthanasia, kidney tissue was fixed in buffered neutral formalin and examined using immunofluorescence microscopy. The intensity of the glow was evaluated based on a visual-analog scale. Results. In the group with chronic hyperglycemia without treatment, there was a significant increase in the protein content in daily urine and serum creatinine levels (p&lt;0,05). In the group of animals with chronic hyperglycemia without treatment, there was a significant decrease in the expression of Klotho protein compared to the group of intact animals during immunofluorescence analysis. In the group treated with the GABA derivative succicard, there was an improvement in the functional state of the kidneys, accompanied by a significant increase (p≤0,0001) in the area of Klotho-positive material in the epithelium of the convoluted tubules of the kidney in relation to the group of animals with prolonged hyperglycemia without treatment. Conclusion. Prolonged hyperglycemia causes severe renal dysfunction in rats with streptozotocin diabetes: an increase the proteinuria and serum creatinine levels is accompanied by a decrease in the expression of Klotho protein in the kidneys. The GABA derivative succicard with course administration improves kidney function and this effect is accompanied by an increase in the expression of Klotho protein.

Pregabalin use in forensic hospitals and prisons in German speaking countries-a survey study of physicians.

Pregabalin is a gamma-aminobutyric acid (GABA) analog that was approved in the EU in 2004 for the treatment of neuropathic pain, generalized anxiety disorder and epilepsy. Since its introduction, pregabalin abuse and misuse has increased significantly. In Switzerland, clinical reports suggest that pregabalin misuse is common among patients in forensic hospitals and prisons. However, data on pregabalin use is scarce, especially in these settings. Therefore, we conducted a study to explore patterns of pregabalin use among prison and forensic patients. We used a questionnaire to survey physicians working in prison and forensic medicine in German-speaking countries. A total of 131 responses were received. According to the physicians' subjective assessment, 82.5% of them had observed a recent increase in pregabalin use by their patients and 89.1% of them reported that their patients requested pregabalin without a clear medical indication. Patients misusing pregabalin in combination with other illicit substances were observed by 93.3% of the physicians surveyed. According to 73.5% of the physicians surveyed, they had already encountered patients on pregabalin doses of more than 600 mg/day (the maximum recommended daily dose); the highest dose reported was 4,200 mg/day. According to 85.0% of physicians surveyed, they have observed patients experiencing withdrawal symptoms from pregabalin, with the most commonly reported symptoms being displeasure and high aggression. Regarding the nationality of pregabalin-misusing patients, 58.3% of the interviewed physicians reported to be rather in contact with foreign patients, mainly from Northwest Africa (Maghreb). Only 45.0% of the surveyed physicians prescribe pregabalin. Among patients who developed behavioral problems while taking pregabalin, none of the physicians (0.0%) showed a tendency to continue pregabalin at the same dose; all respondents chose to reduce/substitute/discontinue. Our study has provided confirmatory evidence that the use of pregabalin presents a significant issue in forensic and prison medicine across German-speaking countries. Prescribing pregabalin in this field can compound use disorder problems and exacerbate challenges in daily life for those in forensic institutions or prisons. It is necessary that all physicians who prescribe pregabalin are clearly informed about the management (including the risks) of this drug.

Synthesis of chiral 2-(N-Boc-azetidin-3-yl)-2-alkylpropanoic acids as novel GABA derivatives

Synthesis of chiral 2-(N-Boc-azetidin-3-yl)-2-alkylpropanoic acids as novel GABA derivatives

Concise approach to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids. Synthesis of vigabatrin.

γ-Aminobutyric acid (GABA) and GABA derivatives have attracted increased attention over the years in the fields of medicinal chemistry and chemical biology due to their interesting biological properties and synthetic relevance. Here, we report a short synthetic route to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids, including the antiepileptic drug vigabatrin, from readily available donor-acceptor cyclopropanes and ammonia or methylamine. This protocol includes a facile synthesis of 2-oxopyrrolidine-3-carboxamides and their acid hydrolysis to γ-aryl- or γ-alkenyl-substituted GABAs, which can serve as perspective building blocks for the synthesis of various GABA-based N-heterocycles and bioactive compounds.

Asymmetric synthesis of (R)-baclofen and (3S,4S)-tetflupyrolimet via "on water" organocatalytic addition reactions: a tip on catalyst screening.

This work demonstrates asymmetric synthesis of the GABA derivative (R)-baclofen and a new herbicidal mode-of-action inhibitor (3S,4S)-tetflupyrolimet featuring low loading (0.5 mol%) organocatalytic addition reactions of dithiomalonates to nitrostyrenes under "on water" conditions. Importantly, we observed that increasing the hydrophobicity of the catalyst does not guarantee improved catalytic performance under "on water" conditions and the trends in the catalytic efficiency of different HBD catalysts under "on water" conditions (with hydrophobic additives) align more closely with those observed in pure hydrophobic organic solvents. These findings propose a valuable tip for screening organocatalysts in developing asymmetric hydrogen-bonding catalysis under "on water" conditions.

GABAA receptors as plausible molecular targets and mediators for taurine and homotaurine actions.

Dementia and autoimmune diseases are prevalent conditions with limited treatment options. Taurine and homotaurine (HT) are naturally occurring sulfonate amino acids, with taurine being highly abundant in animal tissues, but declining with age in the blood. HT is a blood-brain barrier permeable drug under investigation for Alzheimer's disease. HT also has beneficial effects in a mouse model of multiple sclerosis likely through an anti-inflammatory mechanism mediated by GABAA receptor (GABAAR) agonism in immune cells. While both taurine and HT are structural GABA analogs and thought to be GABA mimetics at GABAARs, there is uncertainty concerning their potency as GABA mimetics on native GABAARs. We show that HT is a very potent GABA mimetic, as it evokes GABAAR-mediated currents with an EC50 of 0.4μM (vs. 3.7μM for GABA and 116µM for taurine) in murine cerebellar granule cells in brain slices, with both taurine and HT having similar efficacy in activating native GABAARs. Furthermore, HT displaces the high affinity GABAAR ligand [3H]muscimol at similarly low concentrations (HT IC50 of 0.16μM vs. 125μM for taurine) in mouse brain homogenates. The potency of taurine and HT as GABAAR agonists aligns with endogenous concentrations of taurine in the blood and with HT concentrations achieved in the brain following oral administration of HT or the HT pro-drug ALZ-801. Consequently, we discuss that GABAARs subtypes, similar to the ones we studied here in neurons, are plausible targets for mediating the potential beneficial effects of taurine in health and life-span extension and the beneficial HT effects in dementia and autoimmune conditions.

A phase I study to evaluate the safety, tolerability, and pharmacokinetics of a novel, potent GABA analog HSK16149 in healthy Chinese subjects.

Purpose: HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HSK16149 after single and multiple doses in healthy Chinese subjects. Methods: The randomized, double-blind, placebo-controlled study comprised two parts: SAD (single ascending-dose study) and MAD (multiple ascending-dose study). A total of 122 healthy subjects were enrolled in this study. HSK16149 capsule or placebo was administered as the protocol required. The safety of the drug was evaluated through clinical examinations and adverse events. Blood and urine samples were collected at the designated time intervals for pharmacokinetic analysis. Results: Subjects were generally well tolerated after HSK16149 administration and the most common treatment-emergent adverse event (TEAEs) was dizziness, which was expected based on the mechanism of action of HSK16149. In SAD, AUC and Cmax were shown to have a dose-proportional relationship in the dose range of 5-120mg. The t1/2 of HSK16149 is 3.7-6.4h. In MAD, after a single and multiple administration of 15-80mg, AUC and Cmax are proportional to the increased dose of HSK16149, and the accumulative ratios of AUC and Cmax at steady-state were 1.05-1.44 and 1.07-1.36, respectively, indicating that HSK16149 only accumulated slightly after repeated administration. Conclusion: HSK16149 was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 80mg twice daily (BID) was suggested as the highest target dose for further clinical development. Clinical Trial Registration: http://www.chinadrugtrials.org.cn, identifier CTR20182535 and CTR20191317.