Program Summary The ideal pain medication would be devoid of the serious side effects associated with the currently used opioids (respiratory depression, constipation, dependence, addiction). Mitragynine is a corynanthe-type indole alkaloid isolated as the major alkaloid component of the leaves of the plant Mitragyna speciosa; a “legal high” sold over the internet as kratom, and is currently unregulated. Mitragynine-related natural products possess affinity for mu opioid receptors and exhibit analgesia in rodent models when given systemically. Mitragynine pseudoindoxyl (MP), is a semi-synthetic analog related to mitragynine, which is more potent of an analgesic compared to mitragynine. This scaffold also behaves as delta antagonist, and as a biased mu agonist towards G-protein transduction systems. MP shows reduced respiratory depression, tolerance and dependence, and no rewarding behavior in mice. Thus, this template represents an excellent starting point for developing analgesics with a superior side effect profile to all clinically used mu opioid analgesics. We will also to create a library of derivatives of MP by using total and semi-synthetic approaches. Detailed pharmacological characterization of these analogs will lead to a substantially better understanding of SAR of MP-type compounds. Our final goal is to characterize the compounds pharmacologically in vitro and in vivo. Analogs will be evaluated for potency and an advantageous side-effect profile (i.e. absent or reduced tolerance, dependence, respiratory depression, constipation, reward and aversion). Physicochemical properties like solubility, stability, permeation and CNS penetration, also will be studied. The long-term objective of this proposal is to understand if G-biased MOR agonism in combination with DOR antagonism can lead to reduced tolerance/physical dependence in multiple rodent pain models (thermal, inflammatory, neuropathic) and also lead to synthesis of non-addicting and non-abusable analgesics. The central hypothesis is to diversify the MP template using our total synthetic/semi-synthetic approaches and prepare compounds with a MOR-DOR mixed agonist-antagonist profile with increased metabolic stability. These goals will be accomplished through an interdisciplinary team with significant experience in medicinal chemistry, synthetic chemistry, pharmacology, neuroscience, drug metabolism and pharmacokinetics.