AZD2066 / AstraZeneca - LARVOL DELTA

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

Location and cell-type specific bias of metabotropic glutamate receptor, mGlu5, negative allosteric modulators. (PubMed, ACS Chem Neurosci) - "Here we show that NAMs such as AFQ056, AZD2066, and RG7090 elicit very different end points when tested in postnatal neuronal cultures expressing endogenous mGlu receptors. Moreover, biotinylation studies reveal that more than 90% of the receptor is intracellular in these neurons. Taken together, these data indicate that the tested NAMs exhibit both location-dependent and cell type specific bias for mGlu5-mediated Ca2+ mobilization which may affect clinical outcomes."

Journal • Autism Spectrum Disorder • CNS Disorders • Depression • Genetic Disorders • Mental Retardation • Mood Disorders • Psychiatry

Detailed in vitro pharmacological characterization of clinically tested negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5). (PubMed, Mol Pharmacol) - "k and k values varied greatly between the nine NAMs (34- and 139-fold, respectively) resulting in long receptor residence times (>400 min) for basimglurant and mavoglurant, medium residence times (10-30 min) for AZD2066, remeglurant, and (RS)-remeglurant, and low residence times (<10 mins) for dipraglurant, F169521, F1699611, and STX107. Negative allosteric modulators (NAMs) have shown promising results in preclinical models but have so far failed in human clinical trials. Here we provide the most comprehensive and comparative molecular pharmacological study to date of nine preclinical/clinical tested negative allosteric modulators (NAMs) at the mGlu5 receptor, which is also the first study to measure binding kinetics and negative allosteric modulation of mGlu5 receptor internalization."

Journal • CNS Disorders

Safety evaluation of the mGluR5 antagonists AZD9272, AZD2066 AND AZD2516 in healthy volunteers and patients with neuropathic pain or major depressive disorder (WCP 2012) - Presentation time: Tuesday, August 28; 9:45 am; P1, N=116; In healthy volunteers the CNS-related AEs increased in frequency with increasing dose and were found to be subject to tolerance development in the AZD2066 multiple ascending dose (MAD) study; AEs were more common among those receiving active drug compared to placebo

P1 data • Pain

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])."

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