University of Florida
Talk Session: SESSION 11: SCAFFOLDS AND PEPTIDOMIMETICS
Date: Wednesday, June 15, 2022
Talk Time: 10:40 am - 11:00 am
Talk Title: Macrocyclic Tetrapeptides Prevent Reinstatement of Opioid-Seeking Behavior
Jane V. Aldrich, Ph.D., joined the University of Florida as professor of medicinal chemistry in 2015 under UF’s preeminence initiative in drug discovery and development. Dr. Aldrich’s research on analogs of opioid peptides has been continuously funded by the National Institute on Drug Abuse for over 25 years, and she has been the principal investigator of over $14 million in research grants. Following receiving her Ph.D. in medicinal chemistry, Dr. Aldrich was an NIH postdoctoral fellow at the University of Minnesota where she began her research on opioid peptides. She subsequently rose through the ranks at Oregon State University and the University of Maryland Baltimore prior to moving to the University of Kansas as professor of medicinal chemistry in 2001.
Dr. Aldrich has served the scientific community in multiple capacities. She is currently chair of the NIH Drug Discovery for the Nervous System Study Section and also a Councilor for the Medicinal Chemistry Division of the American Chemical Society. She has also served as chair of the Medicinal Chemistry Division, president of the American Peptide Society, and co-chair of the Gordon Research Conference on the Chemistry and Biology of Peptides. She is currently on the editorial board of the Journal of Medicinal Chemistry and previously was an editor of the journal Letters in Peptide Science.
Opioid misuse is a serious health problem, with 1.6 million Americans meeting the criteria for an opioid use disorder, OUD, and opioid overdose deaths increasing sharply over the last two years. While medications are available to manage OUD, the relapse rate after detoxification can be up to 80%, with stress being a major factor contributing to relapse of drug-seeking behavior. The endogenous kappa opioid system mediates stress responses, and kappa opioid receptor, KOR, antagonists are known to prevent relapse of cocaine-seeking behavior.
We are investigating macrocyclic tetrapeptides related to the KOR antagonist [D-Trp]CJ-15,208 for their potential development as treatments for substance use disorder. A number of analogs of this lead peptide produced KOR antagonism in the CNS after oral administration. Administration of an analog. 30 mg/kg, p.o., prevented stress-induced increases in voluntary consumption of morphine in a two-bottle choice assay, reinstatement of morphine-seeking behavior in a conditioned-place preference assay, and also significantly reduced signs of withdrawal in physically-dependent mice.
Moreover, this analog lacked liabilities, respiratory depression, locomotor effects and reinforcing effects, associated with opioid agonists. These results demonstrate the potential for development of these orally active peptides for the treatment of OUD.
This work was supported by the Defense Health Program, through the Peer Reviewed Medical Research Program under Awards W81XWH- 15-1-0452 and W81XWH-15-1-0464. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.