Research Project
2791774
DESCRIPTION (Adapted from the application): Acute pain states are still mainly treated with opioids, despite their side effects, which include tolerance, dependence, respiratory depression, and constipation. Chronic pain states are not managed well with current pharmacological therapies, such as selective serotonin reuptake inhibitors (SSRIs) and anticonvulsants. Thus, there exists an unmet medical need for superior pharmacological approaches to pain management. A novel receptor, opioid receptor-like 1 (ORL1), with homology to the opioid receptors was recently cloned. Subsequently, the endogenous peptide agonist, nociceptin or orphanin FQ was discovered. Together, nociceptin/orphanin FQ and ORL1 constitute a new neurotransmitter/neuromodulator system in the brain and spinal cord distinct from, but co-existing with, opioid receptor pathways. Nociceptin/orphanin FQ has been shown to produce hyperalgesia and to block opioid-induced analgesia in animals, suggesting that ORL1 antagonists will be analgesic. The applicant has discovered a selective ORL1 antagonist, Co 106284. The applicant proposes to synthesize analogs of Co 106284 to optimize activity at ORL1. The applicant also proposes to evaluate the analgesic potential of Co 106284 and its analogs in animal models of pain states. This information will allow the applicant to decide whether Co 106284 has the potential to become the forerunner of a new class of analgesic agents. PROPOSED COMMERCIAL APPLICATION: Agents for acute and chronic pain states.
