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).
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.