权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Opioid use disorders: UF Pharmacy medications discovery and development

阿片类药物使用障碍：UF Pharmacy 药物的发现和开发

基本信息

批准号：
10525226
负责人：
Christopher R McCurdy
金额：
$ 144.47万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10525226
关键词：
Acclimatization Address Adrenergic Agents Adrenergic Agonists Adrenergic Receptor Affinity Agonist Alkaloids Attenuated Behavioral Behavioral Assay Binding Binding Proteins Biological Assay Biological Availability Blood - brain barrier anatomy Brain Cell Line Cessation of life Characteristics Chemicals Chronic Clonidine Data Dependence Development Dose Drug Interactions Drug Kinetics Drug usage Elements Exhibits FDA approved Female Frequencies Funding Funding Opportunities GTP-Binding Proteins Half-Life Hepatocyte Human Hyperventilation In Vitro Individual Investigation Knowledge Lead Ligand Binding Ligands Liver Microsomes Measures Medicinal Herbs Metabolic Methadone Microsomes Mitragyna Morphine Naltrexone Natural Products Opiate Addiction Opioid Opioid Receptor Opioid agonist Oral Overdose Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Pharmacy facility Phase Plants Plasma Plasma Proteins Preclinical Drug Development Prodrugs Property Rattus Receptor Activation Renal clearance function Respiration Schedule Self Administration Signaling Protein Stimulus Testing Therapeutic Tissues United States Ventilatory Depression Withdrawal Work abuse liability analog antagonist blood-brain barrier penetration design drug discovery drug discrimination efficacy evaluation improved in vivo innovation lofexidine male medication for opioid use disorder metabolic abnormality assessment non-opioid analgesic novel novel strategies novel therapeutics opioid abuse opioid epidemic opioid use opioid use disorder pharmacologic pharmacophore predictive test prevent radioligand receptor respiratory scale up stem

项目摘要

PROJECT SUMMARY This project is submitted under Funding Opportunity Announcement (FOA) Number: RFA-DA-19-002. Opioids have been significantly over-prescribed and are associated with numerous deaths, resulting in the Nation’s current opioid crisis. The FDA recently approved the α2 adrenergic agonist lofexidine as a non-addictive, non-opioid treatment for opioid use disorder. This preclinical drug development effort stems from the psychoactive, natural product, Mitragyna speciosa (kratom), a Thai medicinal herb used as a self-treatment for opioid use disorder. Mitragynine, the plant’s most abundant alkaloid, is a low efficacy µ receptor agonist with G- protein signaling bias. Our preliminary studies suggest that mitragynine has limited abuse liability, and interacts with non-opioid CNS targets including α2 adrenergic receptors, which have not been exploited in its unique mechanism. A single drug (mitragynine) that interacts with both opioid and α2 adrenergic receptors would offer a highly innovative approach for treating opioid use disorder. The work planned here, involving a collaborative, interdisciplinary team, will examine the pharmacophoric elements of mitragynine through synthetic derivatives in an approach that led to the understanding of the essential pharmacophore of morphine. We will use a combination of chemical and prodrug synthesis, in vitro metabolic stability, affinity and efficacy analysis, behavioral assays predictive of receptor mechanism (drug discrimination), abuse (self-administration), and untoward effects (respiratory depression, tolerance, and dependence), and in vivo ADME assays. Mitragynine analogs are expected to yield innovative compounds with a pharmacological mechanism that includes opioid and adrenergic activity. Our efforts to identify the pharmacophoric requirements of mitragynine will lead to templates for the design of novel opioid receptor ligands; this will greatly improve the knowledge of interactions of these structurally novel compounds with opioid receptors and facilitate the development of these ligands as treatments for opioid use disorders. The specific aims of the 2-year UG3 phase are as follows. AIM 1: Identify opioid pharmacophoric requirements of mitragynine analogs through deletion design and analog stability; identify mitragynine prodrugs. AIM 2: Investigate mitragynine analogs in drug discrimination, self-administration, and respiration assays. Analogs exhibiting desired metabolic stability, bioavailability, blood-brain-barrier penetration, binding characteristics, and behavioral activity will be further studied in the UH3 phase as follows. AIM 3: Establish comprehensive in vivo ADME of mitragynine analogs and prodrugs. AIM 4: Assess mitragynine analogs and prodrugs in tolerance, dependence, and withdrawal assays. The results of this project will provide a more comprehensive understanding of the chemical requirements of the putative recognition elements of mitragynine-related ligands at opioid and α2 adrenergic receptors. Ultimately, the potential use of mitragynine and its analogs as templates for the development of a new treatment for opioid use disorders will be realized that may have the potential to yield a safe, effective FDA-approved pharmacotherapy.

项目总结

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of a mouse neuropathic pain model caused by the highly active antiviral therapy (HAART) Stavudine.

由高活性抗病毒疗法（HAART）司他夫定引起的小鼠神经性疼痛模型的表征。

DOI：
10.1007/s43440-021-00262-y
发表时间：
2021
期刊：
Pharmacological reports : PR
影响因子：
0
作者：
Wilkerson,JennyL;Felix,JasmineS;Bilbrey,JoshuaA;McCurdy,ChristopherR;McMahon,LanceR
通讯作者：
McMahon,LanceR

Advances in the In vitro and In vivo pharmacology of Alpha4beta2 nicotinic receptor positive allosteric modulators.

Alpha4beta2烟碱受体正变构调节剂的体外和体内药理学进展。

DOI：
10.1016/j.neuropharm.2020.108008
发表时间：
2020
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Wilkerson,JennyL;Deba,Farah;Crowley,MorganL;Hamouda,AymanK;McMahon,LanceR
通讯作者：
McMahon,LanceR

Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.

DOI：
10.1016/j.toxlet.2019.11.005
发表时间：
2020-02-01
期刊：
Toxicology letters
影响因子：
3.5
作者：
Kamble SH;Sharma A;King TI;Berthold EC;León F;Meyer PKL;Kanumuri SRR;McMahon LR;McCurdy CR;Avery BA
通讯作者：
Avery BA

The use of hypercapnic conditions to assess opioid-induced respiratory depression in rats.

使用高碳酸血症条件评估阿片类药物引起的大鼠呼吸抑制。

DOI：
10.1016/j.vascn.2021.107101
发表时间：
2021-09
期刊：
Journal of pharmacological and toxicological methods
影响因子：
1.9
作者：
Crowley ML;Restrepo LF;Gamez-Jimenez LR;Patel A;Braun T;Pallares VLC;Ho NP;Reeves ME;McCurdy CR;McMahon LR;Hiranita T
通讯作者：
Hiranita T

Unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro-β-erythroidine in nicotine-tolerant mice.

尼古丁耐受小鼠对美加明和二氢-β-赤霉素的烟碱乙酰胆碱受体拮抗剂活性的敏感性意外丧失。