The current status of opiate abuse in the US has been characterized as a ?rapidly evolving public health crisis? requiring the need for new treatments to address the problem. Persistent relapse to addictive drug use is a significant challenge to addiction therapy. Medications targeting the neurobiology underlying relapse offer additional avenues for treatment. Glutamate signaling is critically involved in the dependence on addictive substances. Chronic use of drugs of abuse such as heroin, cocaine and nicotine induces long-lasting changes in glutamate homeostasis that enhance glutamate signaling in key brain areas. Inhibition of the GluN2B subtype of NMDA receptors has been proposed as a valid target for relapse prevention. We propose that NP10679, a pH context-dependent GluN2B selective N-methyl-d-aspartate receptor (NMDAR) inhibitor, could provide benefit as a treatment to prevent relapse to opiate abuse. In this proposal we provide a rationale for targeting GluN2B NMDA receptor inhibition for relapse prevention and present the profile of NP10679 that led to its IND. We then propose experiments to further de-risk the compound to ascertain if the compound deserves further consideration for development in the area of opiate addiction.
Project Terms: addiction; Address; Adverse effects; Area; base; Behavior; Behavioral; behavioral study; Biological Availability; Brain; brain circuitry; Brain Ischemia; Cardiovascular system; Cessation of life; channel blockers; Chronic; Clinical; clinical candidate; Cocaine; Cues; Data; Dependence; Development; disorder later incidence prevention; Dose; Drug abuse; Drug Addiction; drug discrimination; drug misuse; drug of abuse; Drug usage; Evaluation; experimental study; Eyelid structure; glutamatergic signaling; Glutamates; Grant; Heroin; Homeostasis; ifenprodil; Impairment; Infusion procedures; inhibitor/antagonist; Intervention; Learning; Link; male; Measures; Memantine; member; Modeling; Morphine; Motivation; Motor Activity; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; neurobehavioral; Neurobiology; Nicotine; nicotine seeking behavior; novel; Nucleus Accumbens; Olives - dietary; Opiate Addiction; Opioid; opioid abuse; Oral; Overdose; painful neuropathy; Pharmaceutical Preparations; phase 1 study; Population; pre-clinical; preclinical development; prevent; Prevention; Property; Public Health; Rattus; Receptor Inhibition; Relapse; Rewards; Risk; Route; Safety; Sedation procedure; Subarachnoid Hemorrhage; Synapses; Testing; Therapeutic; United States; United States National Institutes of Health; Ventral Tegmental Area; Vertebral column; Work;
