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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33DA036730-03
Application #
9439282
Study Section
Special Emphasis Panel (NSS)
Program Officer
Rapaka, Rao
Project Start
2017-05-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045