Opiate analgesics act at the mu opioid receptor (MOR) in humans to alleviate pain but also to produce unwanted effects such as constipation, respiratory suppression/overdose and addiction. The overall potency and efficacy of an agonist at the receptor may be determined not only by how well the drug binds the receptor but also by how well the receptor engages with intracellular signaling proteins, such as barrestin2. Our studies over the last decade have led us to hypothesize that if a drug could activate the MOR yet not induce barrestin2 interactions with the receptor, then such a drug might be an efficacious analgesic with limited side effects, producing less tolerance, constipation and overdose potential. In the last 5 years, we have generated more than 50 new MOR agonists that activate G protein signaling pathways in a highly biased manner, such that they do not recruit barrestins. Using these compounds, we have tested our hypothesis and have found that this is approach will allow for the separation of analgesic efficacy in vivo from respiratory suppression. We have identified lead candidates and have filed for patent protection of this series of compounds and are currently pursuing clinical development. While certain physiological side effects have been limited, there is no indication thus far that the compounds will not produce reward or be subject to abuse. In this current proposal, we are seeking to test whether they promote drug preference and to further refine candidate compounds and also to introduce affinity at an additional receptor target as a means to introduce abuse deterrence into the compounds. In our initial screens for target selectivity, we noted some affinity for D3 dopamine receptors in a series that was not further pursued (as we focused on MOR selectivity). However, given that D3 dopamine receptors play an important role in maintaining dopamine homeostasis, can greatly impact drug reward thresholds, and have been identified as a drug abuse deterrence target by NIDA, we will focus on optimizing D3 antagonism while maintaining biased MOR agonism in this compound series. In this multidisciplinary study, the Bohn pharmacology laboratory will work in a highly collaborative manner with the Bannister medicinal chemistry laboratory to generate and optimize multiple derivatives on the compound series (Aim 1). We will use several cell-based assays to characterize the signaling parameters induced by these compounds with the goal of finding opiates that maintain G protein over barrestin signaling bias at MOR yet also display D3 DAR antagonism (Aim 2). These compounds will be tested in mouse models to determine if their signaling properties correlate with their ability to produce analgesia with less respiratory suppression and also if dopaminergic behaviors, such as locomotor activity and conditioned place preference are avoided (Aim 3). Finally, in collaboration with Dr. Michael Cameron of Scripps Florida, we will evaluate the DMPK properties of our best candidate compounds. The information garnered from this proposal will prove useful in the clinical development of pain relievers with limited side effects.
The opiate narcotics, including Oxycontin, Percocet, Vicodin and Morphine, are highly effective for managing pain yet produce several unwanted side effects including the severe threat of death by respiratory suppression, or overdose. Thanks to the last round of funding, we have discovered and recently disclosed new opioid compounds (and have identified a clinical lead) that effectively relieve pain without respiratory suppression in mice. In this round of funding we want to determine if these compounds produce drug preference in mice (sign of abuse potential) and make new compounds that have built-in abuse deterrence as a means to control pain without addiction liability.
|Kennedy, Nicole M; Schmid, Cullen L; Ross, Nicolette C et al. (2018) Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias. J Med Chem 61:8895-8907|
|Hirasawa, Shun; Cho, Min; Brust, Tarsis F et al. (2018) O6C-20-nor-salvinorin A is a stable and potent KOR agonist. Bioorg Med Chem Lett 28:2770-2772|
|Schmid, Cullen L; Kennedy, Nicole M; Ross, Nicolette C et al. (2017) Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. Cell 171:1165-1175.e13|
|Rankovic, Zoran; Brust, Tarsis F; Bohn, Laura M (2016) Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett 26:241-250|
|Bohn, Laura M; Zhou, Lei; Ho, Jo-Hao (2015) Approaches to Assess Functional Selectivity in GPCRs: Evaluating G Protein Signaling in an Endogenous Environment. Methods Mol Biol 1335:177-89|
|Luttrell, Louis M; Maudsley, Stuart; Bohn, Laura M (2015) Fulfilling the Promise of ""Biased"" G Protein-Coupled Receptor Agonism. Mol Pharmacol 88:579-88|
|Raehal, Kirsten M; Bohn, Laura M (2014) ?-arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia. Handb Exp Pharmacol 219:427-43|
|Zhou, Lei; Bohn, Laura M (2014) Functional selectivity of GPCR signaling in animals. Curr Opin Cell Biol 27:102-8|