Preclinical validation of mGlu2 PAMs in alcohol use disorder
mGlu2 PAM 在酒精使用障碍中的临床前验证
基本信息
- 批准号:10815668
- 负责人:
- 金额:$ 97.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-20 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AbstinenceAcuteAdultAdverse eventAffectAgonistAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholsAmygdaloid structureAttenuatedBasal GangliaBehaviorBlindedBrain regionCause of DeathCessation of lifeChronicClinical ResearchCorpus striatum structureCoupledCuesDataDevelopmentDevicesDisulfiramDoseDouble-Blind MethodDown-RegulationDrug KineticsDrug usageEconomic BurdenElectroencephalographyEmergency SituationEthanolEthanol dependenceExclusionExposure toGTP-Binding ProteinsGlutamatesGoalsHealthHippocampusHomeostasisHumanImplantIntoxicationInvestigational New Drug ApplicationMaximum Tolerated DoseMedicalMedicineMetabotropic Glutamate ReceptorsModelingMusNaltrexoneNeuronsNeurotransmittersOutcomePathologyPatientsPharmaceutical PreparationsPharmacological TreatmentPhasePlacebo ControlPlasmaPlayPrefrontal CortexRandomizedRattusRelapseReportingResearchResearch PersonnelRodentRodent ModelSelf AdministrationSerious Adverse EventSeveritiesSignal TransductionSleepSleep FragmentationsSleep disturbancesSmokerSocietiesStressSubstance Use DisorderSurveysSymptomsSystemTestingToxic effectUnited StatesUnited States Food and Drug AdministrationUniversitiesValidationVisitWithdrawalacamprosatealcohol abuse therapyalcohol effectalcohol relapsealcohol seeking behavioralcohol use disorderanxiety-related disordersassociated symptomattenuationbinge drinkingchronic alcohol ingestionclinical developmentdrug actiondrug misuseeffective therapyeffectiveness validationexperienceforestin vivomedical schoolsmetabotropic glutamate receptor 2multidisciplinarynegative emotional statenon-smokernovelnovel drug classnovel therapeutic interventionpositive allosteric modulatorpre-clinicalpreclinical developmentpreclinical studypresynapticrelapse preventionsmall moleculesmoking cessationvaporwireless
项目摘要
PROJECT SUMMARY
Alcohol Use Disorder (AUD) continues to be a significant problem, affecting 28.3 million adults in the United
States, and is the third leading preventable cause of death. Disulfiram, naltrexone, and acamprosate are the only
drugs approved by the Food and Drug Administration, but all three have limited efficacy and several
contraindications. Given the substantial burden on society and the economy ($249 billion in 2010), there is a
clear unmet need for effective and well-tolerated therapies that reduce alcohol dependence and relapse in AUD
patients. AUD is characterized by phases of binge drinking, intoxication, and negative emotional states during
withdrawal. The anticipation of alcohol leads to a repetition of these phases followed by periods of extended
abstinence and frequent relapse. Importantly, each of these phases is accompanied by sleep disturbances (SDs).
Three primary brain regions are involved in AUD-associated behavior: the prefrontal cortex (anticipation), basal
ganglia (binge drinking), and amygdala (withdrawal). Several neurotransmitters are dysregulated in AUD,
including the glutamatergic system. Extensive experimental evidence suggests that glutamate (Glu) critically
modulates the actions of drugs of misuse, including alcohol. Therefore, normalization of aberrant Glu activity
caused by chronic alcohol use potentially represents a novel therapeutic strategy to prevent relapse in AUD. The
activation of metabotropic Glu receptor subtypes 2 and 3 (mGlu2/3) using agonists or positive allosteric
modulators (PAMs) decreases ethanol (EtOH) self-administration (SA) as well as cue-induced reinstatement of
EtOH seeking in rodents. Both alcohol-dependent rodents and humans show downregulation of mGlu2
expression, and many studies suggest that deficiencies in mGlu2 signaling may underlie AUD pathology.
Moreover, preclinical studies indicate that mGlu2/3 activation has promise for treating stress- and anxiety-related
disorders in humans and can systematically augment sleep, symptoms that are comorbid with AUD. We
hypothesize that mGlu2 PAMs represent a promising new class of drugs to treat AUD. To test this hypothesis,
our team has discovered and optimized three small molecule mGlu2 PAMs, SBP-9330, SBP-1315, and
SBP-9220, that show efficacy in multiple models of substance-use disorders. To accomplish this, our specific
aims are (1) Determine the in vivo efficacy of mGlu2 PAMs to decrease EtOH intake in rat models of dependent
and non-dependent EtOH SA, (2) Determine the in vivo efficacy of mGlu2 PAMs to normalize SDs during
withdrawal and abstinence following EtOH SA, and (3) Determine the effect of a fixed dose of EtOH on the PK
profile and maximum tolerated dose of mGlu2 PAMs in rats. We have assembled a multidisciplinary team of
investigators with the expertise and experience to achieve these outcomes. Successful completion of these
studies will facilitate the development of a novel mGlu2 PAM towards filing of an investigational new drug (IND)
application and ultimately, a safe and effective treatment for AUD.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Reto Andreas Gadient其他文献
Reto Andreas Gadient的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Reto Andreas Gadient', 18)}}的其他基金
Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptors 2 & 3 (mGlu2/3) for the Treatment of Depression
代谢型谷氨酸受体 2 的负变构调节剂 (NAM)
- 批准号:
10183332 - 财政年份:2020
- 资助金额:
$ 97.39万 - 项目类别:
相似海外基金
Un/kindness, shame & resistance: the care of inpatients in NHS adult acute mental health units and how it might be improved
Un/善良,羞耻
- 批准号:
2885806 - 财政年份:2023
- 资助金额:
$ 97.39万 - 项目类别:
Studentship
Post-Acute Care Transitions for Older Adult Medicare Beneficiaries with Serious Mental Illness
患有严重精神疾病的老年医疗保险受益人的急性后护理过渡
- 批准号:
10772386 - 财政年份:2023
- 资助金额:
$ 97.39万 - 项目类别:
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
474619 - 财政年份:2022
- 资助金额:
$ 97.39万 - 项目类别:
Operating Grants
Investigating the impact acute inhalation of cannabis with a high content of delta-9-tetrahydrocannabinol has on myelination and microglia in adult and aged mice
研究急性吸入高含量 delta-9-四氢大麻酚的大麻对成年和老年小鼠髓鞘形成和小胶质细胞的影响
- 批准号:
485965 - 财政年份:2022
- 资助金额:
$ 97.39万 - 项目类别:
Studentship Programs
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
466358 - 财政年份:2022
- 资助金额:
$ 97.39万 - 项目类别:
Operating Grants
Metabolomics for prediction of cisplatin mediated acute kidney injury: a Canadian multi-centre adult and pediatric study
预测顺铂介导的急性肾损伤的代谢组学:加拿大多中心成人和儿童研究
- 批准号:
402040 - 财政年份:2019
- 资助金额:
$ 97.39万 - 项目类别:
Operating Grants
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
$ 97.39万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Causal effect of time-varying driving pressures on mortality in mechanically ventilated, adult patients with acute respiratory distress syndrome
时变驱动压力对机械通气成年急性呼吸窘迫综合征患者死亡率的因果影响
- 批准号:
377313 - 财政年份:2017
- 资助金额:
$ 97.39万 - 项目类别:
Studentship Programs
Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia
SETBP1 在成人 Ph 急性淋巴细胞白血病中的作用
- 批准号:
9315111 - 财政年份:2016
- 资助金额:
$ 97.39万 - 项目类别:
Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
成体颗粒细胞的急性抑制及其抗抑郁作用
- 批准号:
8734273 - 财政年份:2013
- 资助金额:
$ 97.39万 - 项目类别:














{{item.name}}会员




