Neoclerodanes as Novel Opioid Ligands
Addiction to cocaine and methamphetamine, highly addictive psychostimulants, is associated with substantial neuropsychiatric co-morbidity, and also enhances transmission of HIV-1, hepatitis B and C and thus causes massive public health costs. There are currently no FDA-approved treatments for psychostimulant addiction. This project seeks develop neoclerodane-derived kappa opioid receptor (KOR) ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse, as well as neuropsychiatric disorders (including anxiety, depression and stress-related disorders such as PTSD). The design, synthesis, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors.
Functionally Selective KOR Ligands
Functional selectivity, also known as “biased agonism”, is a term used to describe the ability of drugs, acting at the same receptor subtype, to differentially regulate the activity of each of the multiple signaling cascades coupled to the receptor. The underlying mechanism for functional selectivity is based upon the formation of ligand-specific receptor conformations that are dependent upon ligand structure and that have differential ability to regulate various cellular signal transduction molecules. We are examining structure-activity relationships of functionally selective KOR ligands utilizing a physiologically- and therapeutically-relevant system to guide compound development to maximize analgesic efficacy.
Receptor Type Protein Tyrosine Phosphatase D (PTPRD) Ligands
Therapies for opiate use disorders remain suboptimal in ways that are now a focus of national attention. Genetic, molecular biological and pharmacological evidence in humans and mouse models indicate that PTPRD is a target for the development agents for opioid dependence and stimulant dependence. We are synthesizing and testing improved PTPRD ligands that reduce cocaine reward as we test effects on opiate reward, providing novel drug candidates for progression to new human anti-addiction pharmacotherapies for these two substance use disorders.
Agents for Synthetic Opioid Overdose
Fentanyl is a synthetic opioid that is approximately 100 times stronger than morphine and is used for the treatment of pain, as well as an adjuvant for anesthesia. It is also considered an incapacitating agent, a chemical that produces a disabling condition that persists for hours to days after exposure has occurred, such as in an unexpected chemical attack. As an opioid, fentanyl depresses the central nervous system and respiratory functions, and can be lethal by respiratory depression. Due to its high potency, ingestion of just a few milligrams of fentanyl or other synthetic opioid can be deadly to an opioid naïve individual. Furthermore, first responders at a chemical attack site who come in contact with free base fentanyl analogues are at significant risk for life- threatening toxicities. We are currently developing improved opioid receptor antagonists with the potential to treat overdose by fentanyl and related analogues in individuals at high risk of exposure.
