rislenemdaz (CERC-301) / Avalo Therap, Merck (MSD) - LARVOL DELTA

Characterization of (R)- and (S)-[F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors. (PubMed, ACS Chem Neurosci) - "A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers...Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, (R)-[F]OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies."

Journal • Preclinical • CNS Disorders • GRIN2B

Ketamine and Other Glutamate Receptor Modulating Agents for Treatment-Resistant Depression: A Systematic Review of Randomized Controlled Trials. (PubMed, Iran J Psychiatry) - "Based on the included studies, compelling evidence was found for ketamine (with or without electroconvulsive therapy, intravenous or other forms), nitrous oxide, amantadine, and rislenemdaz (MK-0657); the results for MK-0657, amantadine, and nitrous oxide were only based on one study for each. Lithium, lanicemine, D-cycloserine, and decoglurant showed mixed results for efficacy, and, riluzole, and 7-chlorokynurenic acid were mostly comparable to placebo...Nevertheless, ketamine could be used as an efficacious drug in TRD; still, additional studies are needed to delineate the optimum dosage, duration of efficacy, and intervals. Further studies are also recommended on the effectiveness of glutamatergic system modulators other than ketamine on treatment-resistant depression."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

Investigational Drugs for the Treatment of Depression (Part 2): Glutamatergic, Cholinergic, Sestrin Modulators, and Other Agents. (PubMed, Front Pharmacol) - "Esketamine for treatment-resistant major depression and brexanolone for post-partum depression are two exceptions from the monoaminergic model, although their use is still limited by high costs, unique way of administration (only intravenously for brexanolone), physicians' reluctance to prescribe new drugs, and patients' reticence to use them. Glutamatergic neurotransmission is explored based on the positive results obtained by intranasal esketamine, with subanesthetic intravenous doses of ketamine, and D-cycloserine, traxoprodil, MK-0657, AXS-05, AVP-786, combinations of cycloserine and lurasidone, or dextromethorphan and quinidine, explored as therapeutic options for mono- or bipolar depression. Sestrin modulators, cholinergic receptor modulators, or onabotulinumtoxinA have also been investigated for potential antidepressant activity. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost 7 decades of..."

Review • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. (PubMed, Cochrane Database Syst Rev) - "Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy."

Clinical • Journal • Review • CNS Disorders • Depression • Epilepsy • 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

A Study of Intermittent Doses of CERC-301 in MDD (clinicaltrials.gov) - P2; N=96; Not yet recruiting; Sponsor: Cerecor Inc

New P2 trial • Biosimilar

Preclinical Evaluation of Benzazepine-Based PET Radioligands (R)- and (S)-C-Me-NB1 Reveals Distinct Enantiomeric Binding Patterns and Tightrope Walk between GluN2B- and Sigma1 Receptor-Targeted PET Imaging. (PubMed, J Nucl Med) - "Coincubation of the GluN2B-antagonist CERC-301 (1 μM) reduced cortical but not cerebellar binding, demonstrating the specificity of (R)-C-Me-NB1 binding to the human GluN2B-containing NMDA receptor...(R)-C-Me-NB1 is a highly selective and specific PET radioligand for imaging the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor. The entirely different receptor binding behavior of (R)-C-Me-NB1 and (S)-C-Me-NB1 raises awareness of a delicate balance that is underlying the selective targeting of either GluN2B-carrying NMDA or σ1 receptors."

Journal • Preclinical • CNS Disorders

Rislenemdaz treatment in the lateral habenula improves despair-like behavior in mice. (PubMed, Neuropsychopharmacology) - "Specific knockdown of BDNF in the LHb prevented CRS-induced despair-like behavior, while preventing CRS-induced increases in BDNF and c-Fos expression in the LHb. Together these results suggest that Ris may exert its antidepressant effects through affecting the LHb such as downregulating BDNF expression in the LHb."

Journal • Preclinical • BDNF

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

NMDA Antagonists for Treatment-Resistant Depression. (PubMed, Handb Exp Pharmacol) - "...Of the other investigational agents, CERC-301 and rapastinel remain in clinical development...Research is still needed to determine the appropriate dose, schedule, and ways to mitigate against unwanted side effects of NMDA receptor blockade. These hurdles need to be overcome before ketamine and similar agents can be prescribed routinely to patients."

Journal

Cerecor announces positive final results of CERC-301 in the treatment of neurogenic orthostatic hypotension (OH) (GlobeNewswire) - "Dr. Stuart Isaacson...noted, 'These robust and sustained blood pressure results make CERC-301 an exciting and promising compound for the treatment of nOH. The fact that these improvements in blood pressure upon standing are seen at least to, and perhaps beyond, six hours post dose may represent a significant step forward in novel treatment options for patients suffering from the debilitating symptoms of nOH.'"

Media quote

Glutamatergic Modulators in Depression. (PubMed, Harv Rev Psychiatry) - "These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578])."

Journal

Cerecor Announces CERC-301 Granted U.S. Patent (GlobeNewswire, Cerecor, Inc.) - "Cerecor Inc...announced that the U.S. Patent and Trademark Office issued U.S. Patent No. 10,202,363 ("the ‘363 patent") on Feb. 12, 2019, which is directed to CERC‑301, an oral, NR2B-specific, NMDA receptor antagonist."

Patent