Post-translational regulation of opioid and cannabinoid receptors

阿片类药物和大麻素受体的翻译后调节

• 批准号: 9249714
• 负责人: Lakshmi A Devi
• 金额: $ 49.82万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249714
• 关键词: Absence of pain sensation; Adverse effects; Affinity; Agonist; Analgesics; Antidepressive Agents; Award; Behavior; Biological Assay; CNR1 gene; Cannabinoids; Cell Communication; Cell physiology; Cells; Central Nervous System Diseases; Complex; Computer Simulation; Dependence; Dimerization; Disease; Drug Addiction; Drug abuse; Exhibits; Funding; G-Protein-Coupled Receptors; Goals; Grant; Homology Modeling; Hyperalgesia; Hypothalamic structure; In Vitro; Ligands; Mediating; Morphine; Mus; Names; Natural Products; Neuropeptide Receptor; Neuropeptides; Normal Cell; Opioid; Opioid Receptor; Pain; Pain management; Pathway interactions; Peptides; Pharmacology; Physiological; Physiological Processes; Play; Post-Translational Regulation; Preparation; Prevention; Property; Proteins; Pruritus; Regulation; Research; Rewards; Role; Signal Transduction; System; Technology; Testing; Therapeutic; Work; addiction; allodynia; analog; base; cannabinoid receptor; chemotherapy; dimer; feeding; high throughput screening; in vitro Assay; in vivo; neurotransmission; new therapeutic target; novel; novel therapeutics; optogenetics; painful neuropathy; receptor; scaffold; screening; small molecule; targeted treatment; tool

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: μOR-δOR heteromer ligands: During the base grant period, we used high throughput screening (HTS) to identify small molecule agonists of the μOR-δOR 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 μOR-δOR 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 μOR-δOR heteromer selective antagonist will be a valuable tool for the demonstration of the physiological significance of these heteromers in vivo. CB1R-δOR ligands: We have demonstrated CB1R-δOR 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-δOR-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 μOR but not δOR 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 κOR 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 κOR 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.

我研究的长期目标是研究调节细胞间通讯和神经传递的基本机制，重点是确定预防和/或治疗药物滥用的新治疗靶点和治疗方法。我们最初的研究集中在阿片类药物和大麻素系统上，导致受体相互作用复合物作为新的治疗靶点的鉴定，以及靶向异聚体的小分子的鉴定。MERIT奖使我能够将研究范围扩大到奖励通路中的其他受体系统，从而发现了两种全新的神经肽受体系统。在延期期间，我打算进行基础资助中描述的研究以及新发现的受体系统-这些描述如下。