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MOR/DOR Heterodimer Antagonists: A Novel Treatment for Opioid Dependence

MOR/DOR 异二聚体拮抗剂：阿片类药物依赖的新型治疗方法

基本信息

批准号：
9918310
负责人：
MICHAEL M MORGAN
金额：
$ 89.8万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918310
关键词：
Acute Pain Affinity Applications Grants Behavioral Behavioral Model Binding Brain Buprenorphine Characteristics Chronic Clinical Clinical assessments Data Dependence Development Dose Drug Delivery Systems Drug Kinetics Female Fentanyl Formulation Funding Funding Mechanisms Goals Home environment In Vitro Investigational Drugs Lead Length Ligands Link Masks Metabolic Methadone Methods Microinjections Modeling Morphine Mus Nylons Opiate Addiction Opioid Opioid Analgesics Opioid replacement therapy Oxymorphone Pain Patients Peptides Pharmaceutical Preparations Phase Physiology Program Development Rattus Receptor Signaling Rewards Rodent Running Safety Series Signal Transduction Testing Therapeutic Therapeutic Uses Toxic effect Withdrawal Withdrawal Symptom blood-brain barrier penetration chronic pain combat daily functioning delta opioid receptor design drug development effective therapy experimental study flexibility glycosylation high reward high risk improved innovation male mouse model nanoformulation nanoparticle novel novel strategies novel therapeutics opiate tolerance opioid overdose opioid use opioid withdrawal pain model pain patient pharmacophore prevent radioligand research clinical testing side effect tool tyrosyl-proline

项目摘要

ABSTRACT Tens of thousands of people die each year from opioid overdose. Many of these people began taking opioids for pain. A critical treatment goal is to reduce the development of opioid dependence either by enhancing opioid analgesia so lower doses can be used or by blocking withdrawal symptoms. Opioid substitution therapy, in which long-lasting opioids such as methadone and buprenorphine are substituted for potent short acting opioids, requires continuous administration to mask opioid withdrawal without reducing opioid dependence. A potentially new approach is suggested by the finding that chronic opioid administration increases the formation of the mu-delta opioid receptor heterodimer (MDOR), and disrupting signaling from these heterodimers appears to enhance opioid antinociception and reduce dependence. These findings suggest that an MDOR antagonist may be especially effective in reducing dependence by limiting opioid tolerance and preventing opioid withdrawal. We created a novel series of potential selective peptide MDOR antagonists to test this hypothesis. These novel antagonists connect low affinity MOR (H-Tyr-Pro-Phe-D1Nal-NH2) and moderate affinity DOR (Tyr-Tic-OH) pharmacophores with a variable length (15-42 atom) flexible polyamide spacer. Our preliminary in vitro data using radioligand binding and 35S-GTPγS shows selectively targeting of the MDOR, with a selectivity ratio of ~89 fold for our best compound, D24M. Microinjection of D24M into the mouse brain selectively increased opioid antinociception in models of acute and chronic pain while strongly decreasing morphine withdrawal. These preliminary findings suggest that D24M could reduce opioid dependence by enhancing opioid antinociception, reducing opioid tolerance, or directly inhibiting opioid withdrawal. Although this completely new class of ligand is promising, the efficacy and translatability of MDOR antagonists depends on the ability to reduce dependence in the absence of disruptive side effects. The UG3 phase of this application will vigorously assess the ability of D24M to reduce dependence in male and female mice and rats. Indications supported by mouse models will be tested using the highly novel home cage wheel-running test in rats to determine the effect of D24M on normal daily function. Male and female rats with and without chronic pain will be included to mimic the clinical situation of pain patients who transition to dependence. If these studies are successful in showing that the D24M can reduce dependence (the UG3 milestone), then new derivatives of D24M to improve MDOR potency, selectivity, metabolic stability, and blood-brain barrier (BBB) penetration via glycosylation and nanoparticle formulation will be developed (UH3 phase). The ultimate goal is to develop an optimized drug ready for Investigational New Drug (IND)-enabling studies and clinical testing. These proposed studies are high-risk, high-reward, with a brand new class of therapeutic drugs to be tested in highly innovative rodent behavioral models. Our plan to assess D24M, the novel MDOR antagonist, and develop new drugs to reduce opioid dependence is well suited to the UG3/UH3 mechanism.

摘要

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Morphine restores and naloxone-precipitated withdrawal depresses wheel running in rats with hindpaw inflammation.

DOI：
10.1016/j.pbb.2021.173251
发表时间：
2021-10
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
0
作者：
Morgan MM;Ataras K
通讯作者：
Ataras K

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling.

DOI：
10.1097/j.pain.0000000000002320
发表时间：
2022-01-01
期刊：
Pain
影响因子：
7.4
作者：
Keresztes A;Olson K;Nguyen P;Lopez-Pier MA;Hecksel R;Barker NK;Liu Z;Hruby V;Konhilas J;Langlais PR;Streicher JM
通讯作者：
Streicher JM

Use of home cage wheel running to assess the behavioural effects of administering a mu/delta opioid receptor heterodimer antagonist for spontaneous morphine withdrawal in the rat.

使用式家用笼子跑步来评估施用MU/Delta阿片受体异二聚体拮抗剂的行为效应，以便大鼠自发性吗啡戒断。