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The γ-aminobutyric acid (GABA) type B receptor (GABA B -R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA A 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 GABA B1 and GABA B2 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.

This study aimed to develop a novel oral drug delivery system for gastroretentive sustained drug release by using a capsular device. A capsular device that can control drug release rates from the inner immediate release (IR) tablet while floating in the gastric fluid was fabricated and printed by a fused deposition modeling 3D printer. A commercial IR tablet of baclofen was inserted into the capsular device. The structure of the capsular device was optimized by applying a design of experiment approach to achieve sustained release of a drug while maintaining sufficient buoyancy. The 2-level factorial design was used to identify the optimal sustained release with three control factors: size, number, and height of drug-releasing holes of the capsular device. The drug delivery system was buoyant for more than 24 h and the average time to reach 80% dissolution (T 80 ) was 1.7-6.7 h by varying the control factors. The effects of the different control factors on the response factor, T 80 , were predicted by using the equation of best fit. Finally, drug delivery systems with predetermined release rates were prepared with a mean prediction error ≤ 15.3%. This approach holds great promise to develop various controlled release drug delivery systems.

Baclofen is a racemic mixture that is commonly used for the treatment for spasticity. However, the optimal dose and dosing interval to achieve effective cerebral spinal fluid (CSF) concentrations of baclofen are not known. Moreover, it is unclear if there are differences in the ability of R- or S-baclofen to cross the blood-brain barrier and achieve effective CSF concentrations. We have validated a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with improved selectivity and sensitivity for the simultaneous quantitation of R- and S-baclofen and metabolites in plasma and CSF. Protein precipitation by acetonitrile was utilized to obtain an acceptable recovery of the analytes. The detection and separation of analytes was achieved on a 48 °C-heated Crownpak CR(+) column (150 mm × 4.0 mm, 5μ) with elution using 0.4% formic acid (FA) in water and 0.4% FA in acetonitrile as the mobile phase running at a flow rate of 1.0 mL/min. Accurate quantitation was assured by using this MS/MS method with atmospheric pressure chemical ionization in multiple reaction monitoring (MRM) mode. Therefore, this method is enantioselective, accurate, precise, sensitive, reliable, and linear from 1 to 1500 ng/mL for baclofen and 2 to 4000 ng/mL for the metabolites. An additional method was developed to separate racemic baclofen 3-(4-chlorophenyl)-4 hydroxybutyric acid metabolites for individual concentration determination. Both validated methods were successfully applied to a clinical pharmacokinetic human plasma and CSF study evaluating the disposition of baclofen and metabolites.

Bisphenol A (BPA) is an estrogen-mimicking chemical that can be selectively detected in water using a chemical sensor based on molecularly imprinted polymers (MIPs). However, the utility of BPA-MIPs in sensor applications is limited by the presence of non-specific binding sites. This study explored a dual approach to eliminating these sites: optimizing the molar ratio of the template (bisphenol A) to functional monomer (methacrylic acid) to cross-linker (ethylene glycol dimethacrylate), and esterifying the carboxylic acid residues outside of specific binding sites by treatment with diazomethane. The binding selectivity of treated MIPs and non-treated MIPs for BPA and several potential interferents was compared by capillary electrophoresis with ultraviolet detection. Baclofen, diclofenac and metformin were demonstrated to be good model interferents to test all MIPs for selective binding of BPA. Treated MIPs demonstrated a significant decrease in binding of the interferents while offering high selectivity toward BPA. These results demonstrate that conventional optimization of the molar ratio, together with advanced esterification of non-specific binding sites, effectively minimizes the residual binding of interferents with MIPs to facilitate BPA sensing., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.