Investigation of 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 drug-resistant tuberculosis, and thus causes massive public health costs. There are currently no FDA-approved treatments for psychostimulant addiction. Recent evidence shows that that ê opioid (KOP) receptors (and their endogenous high-efficacy agonist neuropeptides, the dynorphins) are involved in the modulation of major abuse-related effects of psychostimulants, and particularly relapse. The plant-derived hallucinogen, salvinorin A (a neoclerodane), is a structurally unique KOP-agonist, from the mint Salvia divinorum. Reference KOP-r agonists and salvinorin A can decrease certain psychostimulant-induced effects, but these desirable actions are accompanied by undesirable effects, including the aforementioned hallucinations and sedation. Selected novel semi-synthetic neoclerodanes from the previous period of this Project have potential as “lead” pharmacotherapeutic agents for psychostimulant addiction, as shown by their in vitro and in vivo profiles in translational models, including a reduced burden of undesirable behavioral effects. The central hypothesis of this proposal is that iterative structural modification of these neoclerodane “leads” will generate novel opioid receptor ligands with the potential to treat psychostimulant addiction, relapse, and co-morbid neuropsychiatric disorders. The Specific Aims of this proposal are (1) discover novel semi-synthetic neoclerodanes acting at KOP-r, including an innovative synergistic focus on synthetic compounds, based on the trans-decalin core of salvinorin A, (2) determine the biological activity of compounds in vivo in robust translational models, iteratively with Aim 1. These in vivo models crucially include a translational neuroendocrine biomarker of KOP-r effects, and a complementary evaluation of undesirable sedation-like effects of such ligands. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The iterative design, synthesis and in vivo translational evaluation of these novel molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with KOP-r, a major target for psychostimulant addiction pharmacotherapy, and co-morbid neuropsychiatric disorders.