The long-term goal of my research has been to investigate the fundamental mechanisms modulating cell-cell communication and neurotransmission with a focus on identifying novel therapeutic targets and therapeutics for the prevention and/or treatment of drug abuse. Our initial studies, which were focused on the opioid and cannabinoid systems, led to the identification of receptor interacting complexes as novel therapeutic targets as well as identification of small molecules targeting heteromers. The MERIT award has enabled me to broaden the scope of research to other receptor systems in the reward pathway and this led to the discovery of two completely new neuropeptide receptor systems. During the extension period I intend to pursue studies described in the base grant as well as the newly characterized receptor systems ? these are described below. Identification of heterodimer-selective ligands as new therapeutics for the treatment of pain: ?OR-?OR heteromer ligands: During the base grant period, we used high throughput screening (HTS) to identify small molecule agonists of the ?OR-?OR heteromer. One of the compounds was found to have analgesic properties comparable to morphine but with reduced tolerance and dependence (Gomes et al., 2013a). Analogs of this compound are being synthesized by chemists at MLPCN (LaJolla, CA). During the MERIT extension period we will test these compounds using in vitro and in vivo assays (analgesia, hyperalgesia, addiction, reward etc). The HTS analysis has also yielded antagonists of the ?OR-?OR heteromer. The screening center has provided us with top 90 hits. We will characterize them using in vitro assays and test the top 5 candidates in mice (analgesia, hyperalgesia, allodynia, addiction, reward etc). A ?OR-?OR heteromer selective antagonist will be a valuable tool for the demonstration of the physiological significance of these heteromers in vivo. CB1R-?OR ligands: We have demonstrated CB1R-?OR heteromers to be a target for the treatment of neuropathic pain (Bushlin et al., 2012; Rozenfeld et al., 2012) and chemotherapy-induced pain (Sierra and Devi, in preparation). We have recently developed an assay that is suitable for HTS. During the MERIT extension period, I plan to carry out HTS analysis for the identification of CB1R-?OR-selective ligands and characterize the top hits for their ability to relieve neuropathic pain. Identification of new therapeutic targets for disorders of reward behaviors: Neuropeptides play important roles in a number of diverse physiological processes. Some of the most abundant neuropeptides found in the hypothalamus are generated from the protein named proSAAS; some of these peptides are involved in modulating feeding, drug addiction other rewarding behaviors. However, the receptor systems activated by these peptides were not known. During the base grant period, we deorphanized receptors for two of the proSAAS-derived peptides (Gomes et al., 2013b; Gomes et al., under review) and identified small molecules by in silico screening using a homology model of the receptor (Wardman et al., under review). We also found that these receptors interact with ?OR but not ?OR and this leads to novel pharmacology suggesting that these complexes could be novel therapeutic targets. During the MERIT extension period, I intend to characterize the properties of these receptors complexes using state-of-the-art technologies (Optogenetics and DREADD), identify & characterize small molecules with high affinity & potency, and use these ligands to explore a role for these receptors in the regulation of reward-related behaviors including addiction. These studies are likely to have a major impact on the field since they open novel therapeutic possibilities for the treatment of a variety of CNS disorders including drug addiction. Identification of natural products with novel scaffolds for the treatment of pain and addiction: Recently, we identified Collybolide (extracted from the mushroom C. maculata), as a highly selective ?OR ligand. We find that Collybolide exhibits biased agonistic activity and a 10-fold higher potency for blocking non-histamine-mediated itch as compared to other KOR agonists. Due to its unique scaffold, Collybolide is amenable to extensive diversification. During the MERIT extension period I plan to work with chemists to generate analogs and characterize them with the intent of identifying compounds targeting ?OR with wanted effects (antipruritis, anti-addiction, antidepressant) and reduced side-effects. During the previous funding cycles we have discovered a novel mechanism (GPCR dimerization) and have identified novel therapeutic targets (recently deorphanized hypothalamic receptors and receptor complexes). During the extension period we intend to demonstrate the relevance of these new systems to normal cell function and to disease states using state-of-the art technologies and identify therapeutics for the treatment of disorders of the reward behaviors including drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA008863-24
Application #
9412818
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wu, Da-Yu
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
24
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Margolis, Elyssa B; Fujita, Wakako; Devi, Lakshmi A et al. (2017) Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor. Neuropharmacology 123:420-432
Reckziegel, PatrĂ­cia; Festuccia, William T; Britto, Luiz R G et al. (2017) A novel peptide that improves metabolic parameters without adverse central nervous system effects. Sci Rep 7:14781
Heimann, Andrea S; Gupta, Achla; Gomes, Ivone et al. (2017) Generation of G protein-coupled receptor antibodies differentially sensitive to conformational states. PLoS One 12:e0187306
Gomes, Ivone; Bobeck, Erin N; Margolis, Elyssa B et al. (2016) Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Sci Signal 9:ra43
Wardman, Jonathan H; Gomes, Ivone; Bobeck, Erin N et al. (2016) Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci Signal 9:ra55
Gupta, Achla; Gomes, Ivone; Bobeck, Erin N et al. (2016) Collybolide is a novel biased agonist of ?-opioid receptors with potent antipruritic activity. Proc Natl Acad Sci U S A 113:6041-6
Gomes, Ivone; Sierra, Salvador; Devi, Lakshmi A (2016) Detection of Receptor Heteromerization Using In Situ Proximity Ligation Assay. Curr Protoc Pharmacol 75:2.16.1-2.16.31
Gomes, Ivone; Ayoub, Mohammed Akli; Fujita, Wakako et al. (2016) G Protein-Coupled Receptor Heteromers. Annu Rev Pharmacol Toxicol 56:403-25
Stockert, Jennifer A; Devi, Lakshmi A (2015) Advancements in therapeutically targeting orphan GPCRs. Front Pharmacol 6:100
Stockton Jr, Steven D; Gomes, Ivone; Liu, Tong et al. (2015) Morphine Regulated Synaptic Networks Revealed by Integrated Proteomics and Network Analysis. Mol Cell Proteomics 14:2564-76

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