Chronic pain syndromes affect 25-35% of populations around the world. The presence of chronic pain generates a massive toll on quality of life, workforce productivity and healthcare resource utilization. Although non-opiate medications have been introduced to treat chronic pain syndromes, many types of chronic/neuropathic pain do not respond to such medications (e.g., cancer-related pain, visceral pain syndromes). Drugs acting at opioid receptors and particularly ? (mu) opioid receptors (e.g., morphine, dilaudid) remain the mainstay of chronic pain therapy. However, these ? opioid receptor targeted drugs carry with them a very substantial burden of side effects, including risk of death by respiratory depression and life- long physical dependence on these compounds. More recent research has discovered that activation of other types of opioid receptors ? (delta) and ? (kappa)] can produce relief from pain. Additionally, it has been discovered that opioid receptors can form multiunit complexes at the cell surface, and activation of one receptor can promote activation of another in such complexes (positive allosteric interaction). Taking advantage of this new knowledge, a """"""""rationally"""""""" designed molecule has been synthesized in Lohocla Research Corporation laboratories that can activate ? and ? opiod receptors and not affect ? receptors. This compound alleviates pain. This application is focused on further improvement of this initial (parent) molecule through molecular modeling-driven medicinal chemistry. Four new molecules which, by design, should have higher affinity and efficacy as agonists at ? and ? receptors, will be synthesized. These compounds will be tested in receptor binding assays and whole cell functional assays to generate a specificity profile and determine biological action and potency. Selected compounds will be used for bioavailability studies, and initial proof of concept studies for reversing pain in animal models of inflammatory pain syndromes. These Phase I SBIR studies should set the stage for further development through the SBIR Phase II program and completion of pre-clinical work for a most promising pain medication.

Public Health Relevance

Neuropathic chronic pain, caused by injury, disease or therapeutic treatments such as cancer chemotherapy, can be debilitating and results in high healthcare costs and lost productivity. Currently available medications are not adequate for treating this type of pain. The goal of the current application is to use current scientific knowledge to rationally design effective anti-chronic pain medications, synthesize and evaluate these medications as a prelude to the standard spectrum of pre-clinical and clinical studies to bring a novel analgesic/antihyperalgesic to pain suffering public.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Rapaka, Rao
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Lohocla Research Corporation
United States
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Tabakoff, Boris; Ren, Wenhua; Vanderlinden, Lauren et al. (2016) A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain. Eur J Pharmacol 784:1-14
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