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Development of CP-analogs as novel treatments for opioid use disorder.

开发 CP 类似物作为阿片类药物使用障碍的新疗法。

基本信息

批准号：
10255890
负责人：
Jeffrey Reich
金额：
$ 31.92万
依托单位：
SPARIAN BIOSCIENCES, INC.
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：
2021-08-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255890
关键词：
Absence of pain sensation Acute Adoption Agonist Attenuated Behavioral Assay Behavioral Model Biological Assay Biological Sciences Brain Buprenorphine Cardiac Cell Line Chemicals Chronic Chronic Disease Clinical Clinical Trials Consumption Country Data Development Discipline Disease remission Dose Drug Industry Drug Kinetics Epidemic GTP-Binding Proteins Goals In Vitro Incidence Ion Channel Lead Ligands Lung Maximum Tolerated Dose Medical Metabolic Methadone Mitragyna Morbidity - disease rate Morphine Morphine Dependence Mus Naloxone Names Natural Products Opioid Opioid Antagonist Opioid agonist Oral Pain Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Physical Dependence Physicians Plants Plasma Prevalence Primary Care Physician Process Property Psychological Dependence Public Health Recovery Risk Safety Sampling Schedule Scientist Social Well-Being Specialist Structure Tail Testing Therapeutic Toxicology Translational Research Treatment Side Effects Ventilatory Depression Water Well in self Withdrawal Work addiction analog base chemical synthesis conditioned place preference delta opioid receptor design drug development effective therapy efficacy evaluation improved in vitro Model in vivo innovation lead candidate mortality mu opioid receptors mu receptors novel novel strategies novel therapeutics opioid misuse opioid overdose opioid therapy opioid use opioid use disorder opioid withdrawal prescription opioid receptor receptor binding scale up screening side effect small molecule standard of care

项目摘要

ABSTRACT Opioid use disorder (OUD) is a chronic disorder characterized by the repeated, compulsive use of opioid drugs with a detrimental impact to one's physical, social, and psychological wellbeing. The use of prescription opiates is often necessary to control moderate to severe levels of pain. However, about 10% of patients prescribed an opiate for a medical condition are at risk for developing OUD. Opiate Use Disorder is a global problem but is at crisis levels in the U.S with significant mortality. It is estimated in this country that about ~11M misuse opioids, ~2M people have OUD and close to 50K died from opioid related overdoses. At Sparian, we have assembled a comprehensive team of accomplished scientists, key clinical opinion leaders, and pharmaceutical industry experts across critical disciplines including translational research, medicinal chemistry, CMC, toxicology and clinical trials in an effort to develop an oral, potent, and selective small molecules for the treatment of OUD. Mitragyna speciosa, a plant commonly known as Kratom, is commonly used in the US as a self-remidy to treat opiate withdrawal and OUD. We have identified and synthesized a distinct new chemical entity based on Kratom named 9-methoxy corynantheidine pseudoindoxyl (9CP). 9CP has a different receptor binding profile and different pharmacology than mitragynine. 9CP is both a potent a MOR agonist and delta antagonist. In acute dosing studies it attenuates precipitated withdrawal, it is not rewarding, does not cause physical dependence, and has limited respiratory depression and tolerance. Our Fast Tract proposal aims to take an innovative pharmacological approach to develop orally active, highly potent and selective 9CP analogs, devoid of unwanted side effects, for the treatment of OUD with a better pharmacotherapeutic profile than either methadone or buprenorphine. It is organized into two coordinated phases that employ a succinct experimental plan and a focused drug development approach. In phase 1, we will use an in vitro and in vivo screening paradigm to select one lead molecule and 5-8 backup molecules with suitable drug-like properties. In phase 2, we will progress the selected lead and confirm our choice though exploratory safety and toxicology studies, while also characterizing our backup compounds to better understand our template mitigating risk. In summary, we propose a novel strategy to develop a new class of agents with potential to provide better therapy for OUD.

摘要