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Development of a Potential Treatment for Polysubstance Use Disorders

开发多物质使用障碍的潜在治疗方法

基本信息

批准号：
10443619
负责人：
Celsey Mackenna St. Onge
金额：
$ 4.03万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443619
关键词：
Affinity Agonist Antipruritics Area Attenuated Behavioral Binding Biological Assay Buprenorphine Cessation of life Characteristics Chemicals Chinese Hamster Ovary Cell Clinical Cocaine Dependence Development Diprenorphine Disease Dose Drug abuse Drug usage Enkephalin, D-Penicillamine (2,5)-FDA approved Fentanyl Food Goals Health Immersion Individual Japan K-Series Research Career Programs Knowledge Label Lead Ligands Link Macaca mulatta Mediation Medical Mentors Methadone Methods Molecular Mus Naloxone Naltrexone Neuraxis ORL1 receptor Opioid Opioid Receptor Opioid agonist Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacological Treatment Pharmacology Population Preclinical Testing Prevalence Property Pruritus Public Health Rattus Research Research Personnel Research Training Rewards Route Schedule Self Administration Solubility Stimulant Structure-Activity Relationship Substance Use Disorder System Tail Testing Therapeutic Time Toxic effect Training United States Water addiction analog antagonist aqueous base behavioral pharmacology blood-brain barrier penetration career chemical synthesis comorbidity delta opioid receptor design doctoral student drug development experience in silico in vitro Assay in vitro testing in vivo in vivo evaluation innovation interest kappa opioid receptors lofexidine mu opioid receptors neurotoxicity novel opioid epidemic opioid overdose opioid use opioid use disorder opioid withdrawal polysubstance use prevent programs radioligand receptor response skills stable cell line stimulant abuse stimulant use stimulant use disorder substance use treatment success therapeutic candidate therapy development

项目摘要

Project Summary The long-term objective of this proposed research is to develop a potent and selective kappa opioid receptor (KOR) agonist/mu opioid receptor (MOR) low-efficacy partial agonist as a potential treatment for polysubstance use disorders. Not only are the opioid epidemic and the misuse/abuse of stimulants both major health concerns on their own, but the two classes of drugs are often used concomitantly, resulting in polysubstance use disorders. More specifically, the use of opioids and stimulants in combination has been shown to increase neurotoxicity. The growing population of people suffering from these use disorders is under-served as there are currently no FDA-approved therapeutics for either stimulant use disorders or polysubstance use disorders. This makes the development of new treatment options imperative. Nalfurafine (NLF), a KOR agonist and MOR partial agonist clinically approved to treat uremic pruritis in Japan, has yielded intriguing pharmacological results; it is responsible for a decrease in both opioid and stimulant self-administration, doesn’t result in tolerance or self-administration when used in isolation, yields conditioned place aversion only at high doses, and importantly does not exhibit dysphoric effects. Despite these promising characteristics, NLF is not suitable for repurposing due to its low distribution in the central nervous system, though it may act as a lead for further exploration and development. Therefore, it is hypothesized that KOR agonist/MOR low-efficacy partial agonist dual ligands will serve as effective medications to treat comorbid opioid and stimulant use disorders; further, it is proposed that studying analogs of NLF will lead to the development of this treatment. In this scenario, a KOR agonist will function to attenuate the rewarding effects of opioids and stimulants discouraging abuse, while a MOR partial agonist will function to prevent any psychotomimetic effects typical of KOR agonists. This hypothesis will be tested in three specific aims. In Aim 1, analogs of NLF will be designed and synthesized. Aim 2 will then facilitate the in vitro testing of designed ligands and controls for binding affinity, selectivity, potency, efficacy, and functional activity. The most promising ligands identified from Aim 2 will be subjected to further testing for the determination of their pharmacodynamic profiles in Aim 3; this will include tests of in vivo functional activity, efficacy, potency, time-course and receptor mediation using warm-water tail immersion assays, as well as determination of behavioral effects via self-administration assays. Success of this program will further understanding of NLF structure-activity relationships and lead to the development of a novel ligand with potential as a treatment for polysubstance use disorders.

项目总结