EVT 101 / Evotec, J&J - LARVOL DELTA

Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia. (PubMed, Eur J Med Chem) - "A series of tryptamine derivatives has been designed and synthesized as novel GluN2B subunit-containing NMDA receptor (GluN2B-NMDAR) antagonists, which could simultaneously manifest the receptor-ligand interactions of representative GluN2B-NMDAR antagonists ifenprodil (1) and EVT-101 (3). Based on in vivo pharmacokinetic and pharmacodynamic studies in C57 mice, compound Z25 exhibited a relatively short half-life and a low F value (3.12 ± 0.01%), while administration of Z25 substantially improved the cognitive performance of mice in a series of tests of cerebral ischemic injury. Overall, these results support the further development of compound Z25 as a potential lead compound to treat the cerebral ischemic injury by antagonizing GluN2B-NMDA receptor."

Journal • Cardiovascular • GRIN2B

Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activity. (PubMed, RSC Med Chem) - "Preliminary calculation results suggest a low affinity for the human ether-a-go-go-related gene ion channel (hERG), a high affinity for which was earlier one of the main obstacles for the development of first-generation NMDA-receptor negative allosteric modulators. The docking study and the molecular dynamics calculations suggest a completely different binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (PubMed, CNS Drugs) - "This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1..."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Gastrointestinal Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry

Inhibition of the ERK1/2 Phosphorylation by Dextromethorphan Protects against Core Autistic Symptoms in VPA Induced Autistic Rats: In Silico and in Vivo Drug Repurposition Study. (PubMed, ACS Chem Neurosci) - "Autistic pups were then given dextromethorphan (10, 15, and 30 mg/kg; ip) and risperidone (2.5 mg/kg; ip) from PND 23 to 43 in different groups...The in silico modeling of dextromethorphan against PPDA, TCN-201, MK-22, EVT-101 on NMDA receptors was also performed...The present study provided experimental evidence for the potential therapeutic role of dextromethorphan in attenuating autism symptomatology in the ASD model of rats. Thus, modulation of the glutamatergic signaling can be a potential target for ASD treatment."

Journal • Preclinical • Autism Spectrum Disorder • Genetic Disorders • CAT • IL10 • IL1B • IL6 • TNFA

Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors. (PubMed, J Physiol) - "•Triheteromeric NMDA receptors contain two GluN1 and two distinct GluN2 subunits and mediate excitatory neurotransmission in the central nervous system. •Triheteromeric GluN1/2B/2D receptors have functional properties intermediate to those of diheteromeric GluN1/2B and GluN1/2D receptors. •GluN1/2B/2D receptors are more sensitive to channel block by ketamine and memantine compared to GluN1/2B receptors in the presence of physiological Mg . •GluN2B-selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B-selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D, but not GluN1/2A/2B receptors. •These insights to the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors."

Journal

Repurposing of cefpodoxime proxetil as potent neuroprotective agent through computational prediction and in vitro validation. (PubMed, J Biomol Struct Dyn) - "In our preliminary work, we explored the binding patterns of ifenprodil and EVT-101, found the key amino acids and summarized the pharmacophores, hoping to find such antagonists that target the two binding modes simultaneously. The accuracy of molecular docking results and binding stability of ligand-receptor complexes were validated through 100 ns molecular dynamics simulation and binding free energy calculation. Afterwards, MTT assay (49.8%±0.1%, 5 μM) on NMDA injured SH-SY5Y cells and evidence of the effect on attenuating Ca influx induced by NMDA were applied to validate the computational results, further investigation showed that 5 could suppress the NR2B upregulation induced by NMDA."

Journal • Preclinical

A comprehensive description of GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonists. (PubMed, Eur J Med Chem) - "And the latter are further divided into amidine derivatives, 4-aminoquinolines, indole derivatives, benzimidazole derivatives, oxamide derivatives, carbamate derivatives, EVT-101 analogues, 1H-pyrrolo[3,2-b]pyridine derivatives, benzazepin derivatives, other heterocyles and radiotracers. This review will provide a comprehensive description including structure, structure-activity relationship (SAR), and pharmacology of novel GluN2B-subtype selective NMDA antagonists to the medicinal chemists, which would be helpful in rational designing effective drugs aimed toward related CNS disease."

Journal • Review • CNS Disorders

Computational investigation of the antagonism effect towards GluN2B-Containing NMDA receptor: Combined ligand-based and target-based approach. (PubMed, J Mol Graph Model) - "Which results in the proposal of two interaction models inside the GluN2B binding cavity for two groups of antagonists. The interaction model of "ifenprodil group" antagonists consists of one hydrophobic group, one H-bond donor, one H-bond acceptor and an aromatic ring, while on the other hand, the interaction model of "EVT101 group" antagonists includes three hydrophobic groups and an aromatic ring."

Journal

Exploring the overlapping binding sites of ifenprodil and EVT-101 in GluN2B-containing NMDA receptors using novel chicken embryo forebrain cultures and molecular modeling. (PubMed, Pharmacol Res Perspect) - "The EVT-101 binding pocket appears to accommodate more structurally different ligands than the ifenprodil-binding site, and contains residues essential in ligand interactions necessary for calcium influx inhibition. For the ifenprodil site, the less effective antagonist (eliprodil) fails to interact with key residues, while in the EVT-101 pocket, difference in potency might be explained by differences in ligand-receptor interaction patterns."

Journal • Preclinical

A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. (PubMed, Drug Discov Today) - "Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217."

Journal • Review