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γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the CNS. GABA exerts its function on both ionotropic ligand-gated GABAA receptors and metabotropic GABAB G-protein coupled receptors (GPCRs). Disruption in the GABAergic system has been associated with numerous neurological and psychiatric disorders in humans. These include developmental dysfunctions, epilepsy, sleep disorders, drug and alcohol dependence, schizophrenia, motor coordination disorders, anxiety, autism, inability to regulate emotions, Huntington's disease, and Parkinson's disease. Hence, developing drugs to act on such a remarkable system can attract much attention and be beneficial. In recent years, there has been colossal attention toward development of allosteric modulators of GPCRs. These compounds provide high selectivity, novel modes of action and may lead to unique therapeutic agents for the treatment of many neurological and psychiatric human disorders. Baclofen, a GABAB receptor agonist, is still the only GABAB receptor approved drug, and is used for the treatment of muscle spasticity associated with spinal cord injury and multiple sclerosis; however, numerous side effects hamper its clinical use. Allosteric modulators, on the other hand, are expected to have a much better side-effect profile than traditional orthosteric drugs. In the current study, in silico and in vitro methods were adopted to screen for potential negative allosteric modulators within the MolPort database. A sequential combination of ligand- and structure-based virtual screening was first performed to reduce the significant number of chemical compounds followed by the in vitro experimental testing. The virtual screening procedure facilitated the selection of 16 hit compounds that were purchased and tested experimentally using an in vitro functional assay. Only one compound, A-8, was tested in a dose-response cAMP assay, and results indicate that it is a negative allosteric modulator. In addition, analysis of the initial test results suggests that A-9 might be a negative allosteric modulator and that A-20 might be a positive allosteric modulator. Further accurate experimental tests are required for these compounds.

aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system (CNS). GABA exhibits its function by binding to either the ionotropic GABAA receptor or the metabotropic GABAB receptor, causing a decrease in activity in the nervous system. Disruption in the GABAergic system has been associated with various neurological conditions, including Alzheimer’s disease, anxiety, depressive disorders, and epilepsy. Currently, there is only one marketed drug that work on the GABAB – receptor, on the orthosteric site to be more specific. The discovery of allosteric modulators for the G-protein coupled receptors provides a promising new strategy with potential for developing novel treatments for a variety of CNS disorders, as they allow for increased drug selectivity and potentially decreased adverse side effects. Homology models of the GABAB receptor were built due to the lack of an experimentally solved three-dimensional structure, and they were used to screen for potentially new allosteric modulators using a combination of structure-based and ligand based virtual screening (in silico) with compounds from the Molport database and DrugBank. 16 compounds were purchased for testing – 8 from each database, and were further investigated and evaluated by experimental in vitro testing. Our results indicate that we have four hits, two from each database (DrugBank: I-4 = Mefloquine and I-10 = Rivaroxaban, Molport: I-23 and I-24) where it seems like I-4, I-23 and I-24 acts like PAMs whereas I-10 acts like a NAM/antagonist. The compounds from DrugBank, especially Mefloquine is of interest due to its well-known adverse effect profile which may be linked to the GABAergic system. Further investigation and confirmation of activity at the GABAB receptor could potentially lead to development of novel drugs as well as important tools for studying the structure and function of the GABAB receptor. And at the same time be used to explain the side effects seen when using Mefloquine.