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.