KCa2 Channel Activators for Opioid Use Disorder

用于治疗阿片类药物使用障碍的 KCa2 通道激活剂

基本信息

批准号：
10511349
负责人：
HEIKE WULFF
金额：
$ 41.99万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511349
关键词：
Abstinence Acute Pain Address Affect Affinity Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome American Apamin Behavior Binding Brain Brain region Calcium-Activated Potassium Channel Calmodulin Cessation of life Chemicals Classification Clinical Cryoelectron Microscopy Crystallization Data Development Disease Docking Drug Design Drug usage Electrophysiology (science)Experimental Models FDA approved Funding Opportunities Goals Helping to End Addiction Long-term Homology Modeling Human Individual Injections Ion Channel Laboratories Length Libraries Ligands Machine Learning Methods Modeling Modification Molecular Morphine Dependence Mus Mutagenesis Neurons Nucleus Accumbens Opiate Addiction Opioid Overdose Pain Penetration Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Play Post-Traumatic Stress Disorders Prevention Publishing Rattus Rodent Rodent Model Role Running Structure Substance Addiction Substance Use Disorder Techniques Testing Therapeutic Therapeutic Agents Validation Ventilatory Depression alcohol seeking behavior base benzothiazole chronic pain comorbidity convolutional neural network craving design experience high throughput screening improved innovation insight novel novel therapeutics opioid misuse opioid therapy opioid use disorder pharmacophore polysubstance use prescription opioid prevent protein complex response screening substance use treatment virtual virtual model virtual screening

项目摘要

Abstract Both human and rodent data showing reduced expression of the small-conductance, calcium- activated potassium channel KCa2.2 (SK2) in the context of morphine and alcohol dependence and withdrawal suggest KCa2 channel activation as a promising therapeutic approach for the treatment of substance use disorders and associated comorbidities. In support of this therapeutic hypothesis, KCa2 channel activators reduce alcohol seeking and intake in rats, while direct injection of the KCa2 channel blocking peptide apamin into the nucleus accumbens, a brain region which plays a crucial role in regulating craving and drug seeking during abstinence, increases alcohol intake in mice. In response to the HEAL Initiative RFA-DA-22-032 Funding Opportunity Announcement, we are here proposing to perform virtual high-throughput-screening with the goal of identifying novel KCa2 activator pharmacophores that are free of the liabilities of the existing unselective benzothiazole-type activators and that could be developed into innovative treatments for opioid use disorders (OUD), a condition that affects more than 3 million Americans. For the implementation of this project, we will draw on our 20 years of experience with the medicinal chemistry of KCa channels. After we initially developed KCa3.1 blockers such as TRAM-34, we later discovered the mixed KCa2/3 activator SKA-31, and the KCa3.1 selective activators SKA-121 and SKA-111. All these compounds, which have been widely used in the field to probe the physiological and pathophysiological roles of KCa channels were designed using classical medicinal chemistry approaches without any structural insight. However, the MacKinnon laboratory recently published the full-length cryo-EM structure of a KCa channel in the closed and two open states and we now have a high-quality structural template available to virtually screen for novel KCa2.2 channel modulators that could be used as pharmacological probes and as leads for the design of drugs for the treatment of OUD. In Aim-1, we will validate our KCa3.1-based KCa2.2 homology model by virtually screening 2000 FDA-approved compounds in two activator binding pockets and experimentally confirm the hits by electrophysiology and mutagenesis. In Aim-2, we will perform a virtual High Throughput Screen (vHTS) of a larger, 130,000-compound library with machine learning (ML) techniques for pose classification and binding affinity prediction. Taken together, these two aims have the potential of 1) identifying a clinically used drug that could be repurposed for OUD and 2) discovering novel KCa2.2 activator pharmacophores that could serve as templates for structure- based-medicinal chemistry optimization aimed at developing OUD treatments with a novel mechanism of action.

抽象的人类和啮齿动物的数据都显示了小传导的表达降低，钙 - 在吗啡和酒精依赖性的背景下，活化的钾通道KCA2.2（SK2）提取表明KCA2通道激活是一种有希望的治疗方法物质使用障碍和相关合并症。为了支持这种治疗假设，KCA2 通道激活剂减少大鼠的酒精寻求和摄入，而直接注射KCA2通道将肽apamin阻塞到伏隔核中，这是一个在大脑区域，在调节戒酒期间的渴望和毒品，增加了小鼠的酒精摄入量。作为回应为了“治愈倡议RFA-DA-22-032资金机会公告”，我们在这里建议进行虚拟的高通量屏幕，目的是识别新型KCA2激活剂没有现有的非选择性苯甲唑型激活剂的责任的药物团这可以发展为阿片类药物使用障碍（OUD）的创新治疗方法这影响了超过300万美国人。为了实施该项目，我们将利用我们的20年经验 KCA通道的药物化学。在我们最初开发了KCA3.1阻滞剂（例如Tram-34）之后，后来，我们发现了混合的KCA2/3激活剂SKA-31，KCA3.1选择性激活剂SKA-121 和SKA-111。所有这些化合物，这些化合物已在现场广泛用于探测 KCA通道的生理和病理生理作用是使用经典药物设计的化学方法无需任何结构洞察力。但是，麦金农实验室最近在封闭和两个开放状态下发布了KCA通道的全长冷冻EM结构，我们现在，有一个可用于屏幕的高质量结构模板，用于新型KCA2.2频道可以用作药理探针的调节剂，并用作设计药物的铅 Oud的处理。在AIM-1中，我们将通过实际上验证基于KCA3.1的KCA2.2同源模型在两个激活剂结合口袋中筛选2000 FDA批准的化合物和实验通过电生理学和诱变确认命中。在AIM-2中，我们将表现出一个虚拟的高度带机器学习（ML）的较大，130,000个库存库的吞吐量屏幕（VHT）姿势分类和结合亲和力预测的技术。两者一起，这两个目标有 1）识别可以重新使用的临床使用的药物和2）发现可作为结构模板的新型KCA2.2激活剂药理基于中的化学优化，旨在通过新颖的方式开发OUD处理作用机理。