Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1

QSAR, ADMET In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Studies of Novel Bicyclo (Aryl Methyl) Benzamides as Potent GlyT1 Inhibitors for the Treatment of Schizophrenia

“…Therefore, the discovery of more clinically effective antipsychotic drugs are still necessary [2]. For this goal, the glycine transporter type 1 (GlyT1) inhibitors approved by the Food and Drug Administration (FDA) are a key therapeutic development strategy to treat a variety of central nervous system (CNS) disorders, in particular schizophrenia and cognitive disorders [3,4]. In this regard, type 1 glycine transporters regulate N-methyl-D-Aspartate (NMDA) receptor function via modulation of glycine concentration at the glutamatergic synapses, but their deficiency may affect the higher central nervous system functions [5,6].…”

“…In this regard, type 1 glycine transporters regulate N-methyl-D-Aspartate (NMDA) receptor function via modulation of glycine concentration at the glutamatergic synapses, but their deficiency may affect the higher central nervous system functions [5,6]. In this paper, a systematic in silico study was performed on 44 GlyT1 inhibitors, which were tested in a locomotor activity assay (LMA) of the MK801 mouse to model the treatment of positive and negative symptoms of schizophrenia [4], by means of the following molecular modeling techniques: first of all, the quantitative structure activity relationships (QSAR) as a technology widely used in drug discovery, indicating ligands with a high affinity for a given macromolecular target and optimizing the quantitative linear and non-linear relationship established between structure and inhibitory activity [7,8]; secondly, in silico ADMET prediction of newly engineered drugs [9]; and third, the molecular docking study as an approach designed in computational chemistry to accelerate drug discovery at the early stages through the detection of typical intermolecular interactions, established between the potent ligands and the responsible protein target [10]. The last step concerns the molecular dynamics (MD) simulation as an efficient technique to investigate the dynamic conformational changes of the selected complexes (active ligands-protein target) [11,12].…”

Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties

“…However, further investigation showed that many of these sarcosine derivatives produced a range of deleterious side effects including ataxia, lateral recumbency, and respiratory depression. , These side effects are likely the result of sustained elevation of glycine in caudal regions of the CNS, where GlyT1 and the glycine receptor (Gly A sites) are colocalized and play an important role in control of motor function and respiration. , More recent efforts to develop GlyT1 inhibitors have focused on non-sarcosine chemotypes. A significant number of these second-generation compounds, exemplified by compounds 3 – 7 , − have appeared in the literature recently, and some of these have demonstrated efficacy in preclinical animal models of cognition, pain, addiction, and anxiety. , In addition, several compounds have advanced into clinical development (including compounds 5 – 7 ), as potential treatments for the negative and cognitive symptoms associated with schizophrenia and as treatments for obsessive compulsive disorder (OCD), depression, addiction, and Parkinson’s disease. ,− To date, no GlyT1 inhibitors have received FDA approval.…”