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The study of γ‐aminobutyric acid B receptor (GABAB) activation is of great interest for several brain disorders. The search of new GABAB receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABAB receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABAB receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABAB receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABAB receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features (ELUMO and T(N...O)) and the energy interaction with GABAB receptor (ETRP278). This model was validated by the QUIK, REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the QLOO, QASYM, R02 and rm2 rules. Finally, six new compounds are proposed (35–40) with high potential to be used as GABAB receptor agonists. [ABSTRACT FROM AUTHOR]

Baclofen (1) is a potent and selective agonist for bicuculline-insensitive GABAB receptors and is used clinically as an antispastic and muscle relaxant agent. In the search for new bioactive chemical entities that bind specifically to GABAB receptors, we report here the synthesis of certain baclofen homologues, namely (R,S)-5-amino-3-arylpentanoic acid hydrochlorides (R,S)-1a–h as well as (R,S)-5-amino-3-methylpentanoic acid [(RS)-1i] to be evaluated as GABABR agonists. Compound 1a is an agonist to GABAB receptors with an EC50 value of 46 μM on tsA201 cells transfected with GABAB1b/GABAB2/Gqz5, being the most active congener among all the synthesized compounds.

Baclofen (1) is a potent and selective agonist for bicuculline-insensitive GABAB receptors and is used clinically as an antispastic and muscle relaxant agent. In the search for new bioactive chemical entities that bind specifically to GABAB receptors, we report here the synthesis of certain baclofen homologues, namely (R,S)-5-amino-3-arylpentanoic acid hydrochlorides (R,S)-1a-h as well as (R,S)-5-amino-3-methylpentanoic acid [(RS)-1i] to be evaluated as GABABR agonists. Compound 1a is an agonist to GABAB receptors with an EC50 value of 46 μM on tsA201 cells transfected with GABAB1b/GABAB2/Gqz5, being the most active congener among all the synthesized compounds. [ABSTRACT FROM AUTHOR]

Abstract: This report summarizes the background and specific objectives for a symposium on the neurobiology of nonhomeostatic eating and drug abuse that was held at the 2004 Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB). The symposium was the first of a series funded by a conference grant from four institutes of the National Institutes of Health. The encompassing goal of the series is to analyze the roles for the biological mechanisms of ingestion in obesity, eating disorders and other theoretically related areas including addiction, depression and schizophrenia. The symptoms and treatments of these diverse pathologies routinely involve aberrations in the mechanisms regulating eating and body weight. The presentations and discussion from this symposium (1) identified changes in neurotransmitter dynamics and gene expression in brain “reward circuits” accompanying learning of behaviors to obtain palatable foods or drugs of abuse; (2) analyzed behavioral findings in animals and humans, and neuroimaging data in humans, supporting treatment with GABAB agonists to reduce craving for drugs of abuse and possibly for highly rewarding foods; and (3) used neuroimaging data in humans to establish novel serotonergic targets for normalizing reward processes and impulse control in anorexia nervosa and bulimia. Overall, the symposium clearly revealed our rapidly broadening understanding of the alterations in the brain at the molecular, cellular and systems levels that are associated with craving and nonhomeostatic consumption of food and drugs of abuse. This knowledge gained largely in animal models translates to novel and better strategies for treating human patients. [Copyright &y& Elsevier]

Depression and cocaine use disorder represent frequent co-current diagnoses and the GABA B receptors are involved in both conditions. This research involved the application of the animal model of depression (bulbectomy, OBX) and cocaine use disorder (self-administration) to assess the efficiency of GABA B receptor agonists, baclofen and SKF-97541, on cocaine rewarding property and reinforcement of seeking-behaviors in rats with depressive phenotype. Additionally, we applied immunoreactive techniques to determine changes in the expression of GABA B receptor subunit 1 and 2 in rats with depression and cocaine addiction. The results obtained the study illustrate that the GABA B receptor agonists reduced the rewarding property of cocaine in both OBX and control (SHAM) rats. Both agonists significantly reduced cue- and cocaine-induced reinstatement in both groups. This is the first report demonstrating a different impact of cocaine abuse on GABA B receptor levels in depressed animals. It was documented that the expression of GABA B1 subunit in the infralimbic cortex increased during self-administration and extinction training in OBX animals. The lower level of expression for this subunit in addictive SHAM rats during self-administration, and increased in extinguished addictive OBX rats was found in the ventrolateral striatum. The expression of GABA B2 subunit changed only in the case of cocaine self-administration paradigm, as a decline of the subunit level in the nucleus accumbens and ventral hippocampus was observed only in OBX rats. The relevance of GABA B receptors in depression and addiction comorbidity is clearly implicated and can open a new era of drug discovery for individuals with dual diagnosis. Image 1 • GABA B receptor agonists reduce cocaine addiction in rats with depressive phenotype. • GABA B2 receptor subunit is related with depressive-like phenotype. • GABA B1 receptor subunit is related to addictive behavior in depressive rats. [ABSTRACT FROM AUTHOR]

The study of γ-aminobutyric acid B receptor (GABA B ) activation is of great interest for several brain disorders. The search of new GABA B receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABA B receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABA B receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABA B receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABA B receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features (E LUMO and T(N…O)) and the energy interaction with GABA B receptor (E TRP278 ). This model was validated by the QUIK, REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the Q LOO , Q ASYM , R 0 2 and r m 2 rules. Finally, six new compounds are proposed (35-40) with high potential to be used as GABA B receptor agonists., (© 2019 John Wiley & Sons A/S.)

Objective: Lesogaberan (AZD3355) is a novel γ-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251)., Design: In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of ≥ 3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline., Results: In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p < 0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels., Conclusions: In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms.