The ability to control pain remains a major problem in medicine and society. According to the Institute of Medicine, chronic pain affects about 100 million American adults, more people than those affected by diabetes, heart disease, and cancer combined. It has been estimated that the costs associated with pain in the USA exceeds $600 billion dollars per year, mainly due to medical treatment and lost productivity. While these expenditures are significant, the costs in terms of suffering and quality of life cannot be adequately calculated. Opioid analgesics, such as morphine and its analogs, have been the mainstay for treatment of pain for thousands of years, and currently represent the gold-standard for pain management. However, clinicians are conservative in prescribing, and patients are conservative in taking, opioids due to valid concerns about adverse effects as well as social and legal issues. As a result, pain is often undertreated, and patients continue to suffer. Endogenous peptides regulate activity within the central nervous system (CNS), and are particularly interesting for the treatment of pain, depression and anxiety. Unfortunately, the clinical usage of peptide-based agents is limited by poor physicochemical (PC) and pharmacokinetic (PK) properties, which restrict penetration into the CNS. Therefore, these peptide-based agents cannot be employed clinically for the treatment of pain. The present proposal aims to develop and employ a new fluorination strategy to rationally improve biophysical properties of peptide-based probes with insufficient drug-like properties, and to allow for these probes to enter the CNS.
Many clinically employed analgesics possess undesired side effects, including convulsions, euphoria, sedation, respiratory depression, constipation, tolerance and dependence. Therefore, clinicians are conservative in prescribing, and patients are conservative in taking, opioids due to valid concerns about adverse effects as well as social and legal issues. As a result, pain is often undertreated, and patients continue to suffer. The present proposal seeks to explore strategies for delivering other small-molecule analgesics with limited side effect profiles into the central nervous system for the treatment of pain.
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| Karad, Somnath Narayan; Pal, Mohan; Crowley, Rachel S et al. (2017) Synthesis and Opioid Activity of Tyr1 -?[(Z)CF=CH]-Gly2 and Tyr1 -?[(S)/(R)-CF3 CH-NH]-Gly2 Leu-enkephalin Fluorinated Peptidomimetics. ChemMedChem 12:571-576 |
