Design of Novel Multivalent Ligands with Unique Biological Activity Profiles for Treatment of Prolonged and Neuropathic Pain without Toxicities
具有独特生物活性特征的新型多价配体的设计,用于无毒治疗长期疼痛和神经性疼痛
基本信息
- 批准号:9073237
- 负责人:
- 金额:$ 5.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddictive BehaviorAddressAdverse effectsAffinityAgonistAmino AcidsAnalgesicsAnimal ModelAnxietyBindingBioavailableBiochemicalBiodistributionBiologicalBiological AssayBiological AvailabilityBlood - brain barrier anatomyChemicalsClinical TrialsCollaborationsComputer-Aided DesignConstipationCyclic AMPDevelopmentDoseEnvironmentEvaluationGoalsHalf-LifeHourHumanLeadLigandsMaintenanceMembraneMetabolicModalityMolecular ConformationMorphineNarcotic AntagonistsNeuromedin K ReceptorOpioidOpioid ReceptorPainPain managementPathway interactionsPenetrationPeptide SynthesisPeptidesPeripheralPharmaceutical PreparationsPharmacologyPharmacotherapyPlasmaPropertyPublic HealthQuality of lifeRattusResearchResearch Project GrantsRewardsSerumSocietiesStructureSubstance PSubstance P ReceptorTimeToxic effectVentilatory DepressionVomitingWorkaddictionanalogaqueousbasebiophysical analysisbiophysical toolschronic paindelta opioid receptordesigndrug seeking behaviorexperimental studyimprovedin vivoin vivo Modelinsightkappa opioid receptorsmotor impairmentnanomolarnovelnovel strategiesnovel therapeutic interventionpainful neuropathypeptidomimeticspharmacophorepreferencereceptorsingle molecule
项目摘要
Summary - Project A:
The goals of this research project are to design and discover novel peptide and peptidomimetic ligands
that are multivalent ligands that can act as agonists at the mu and delta opioid receptors and antagonists
at the neurokinin-1 (NK-1) receptor, all in a single molecule. These ligands can act as potent analgesics
in chronic pain states, including neuropathic pain, using new mechanisms of action, but do not have any
of the toxic side effects of current opioids. For this purpose, we are developing a comprehensive
approach that includes: computer aided design of novel multivalent ligands, asymmetric synthesis of
novel amino acids, design and synthesis of peptides and peptidomimetics with unique conformational
properties, especially in membrane environments, unique biological properties for treatment of pain
without toxicities and tolerance development, and unique abilities to penetrate membrane barriers. We
will pursue these goals, with the following Specific Aims: 1) to design and synthesize novel multivalent
ligands that have potent mu and delta opioid receptor agonist activity neutral and (mu preferring) and
potent NK-1 receptor antagonist activity; 2) in conjunction with the Biochemical Core, to evaluate the
pharmacological activities of these compounds with comprehensive binding affinities and efficacies at
mu, delta and NK-1 receptors (also as needed, kappa opioid receptors and NK-3 receptors); 3) to
evaluate the conformational properties of the best ligands by biophysical studies (NMR, CD, etc.) in
aqueous and membrane environments; 4) in conjunction with the Biochemical and Synthesis Cores, to
evaluate their biological activities in vivo to demonstrate the potency and efficacy in in vivo models of
acute, prolonged and neuropathic pain states, and determine their lack of toxic side effects that are
found in current analgesic drugs, including inhibition of gut transit, emesis, development of addictive
behaviors, lack of respiratory depression and development of tolerance. We also will evaluate their
ability to cross membrane barriers and their stability and biodistribution in vivo. A major goal is to obtain
two or three potent, stable and bioavailable ligands with the desired biological activity profiles for
examination in human clinical trials.
摘要-项目甲:
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 }}
Victor J Hruby其他文献
Victor J Hruby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('Victor J Hruby', 18)}}的其他基金
New Modalities for the Treatment of Pain and Drug Abuse
治疗疼痛和药物滥用的新方法
- 批准号:
9073233 - 财政年份:2017
- 资助金额:
$ 5.65万 - 项目类别:
New Modalities for the Treatment of Pain and Drug Abuse
治疗疼痛和药物滥用的新方法
- 批准号:
9918285 - 财政年份:2017
- 资助金额:
$ 5.65万 - 项目类别:
DESIGN OF NOVEL LIGANDS WITH UNIQUE BIOLOGICAL PROFILES FOR NEUROPATHIC PAIN AND
设计具有独特生物特征的新型配体,用于治疗神经病理性疼痛和
- 批准号:
8025975 - 财政年份:2010
- 资助金额:
$ 5.65万 - 项目类别:
Design of Novel Opiod Peptide Ligands With Unique Biological Profiles
具有独特生物学特征的新型阿片肽配体的设计
- 批准号:
7513577 - 财政年份:2007
- 资助金额:
$ 5.65万 - 项目类别:
相似海外基金
Neuronal regulation of glutamate homeostasis in addictive behavior
成瘾行为中谷氨酸稳态的神经元调节
- 批准号:
364631096 - 财政年份:2017
- 资助金额:
$ 5.65万 - 项目类别:
Research Fellowships
The Effects of Sadness Versus Gratitude on Economic Decision Making and Addictive Behavior
悲伤与感恩对经济决策和成瘾行为的影响
- 批准号:
1559511 - 财政年份:2016
- 资助金额:
$ 5.65万 - 项目类别:
Continuing Grant
Beta-arrestin Regulation of Ghrelin Signaling in Modulating Addictive Behavior
β-抑制素对 Ghrelin 信号传导在调节成瘾行为中的调节
- 批准号:
8811411 - 财政年份:2014
- 资助金额:
$ 5.65万 - 项目类别:
Beta-arrestin Regulation of Ghrelin Signaling in Modulating Addictive Behavior
β-抑制素对 Ghrelin 信号传导在调节成瘾行为中的调节
- 批准号:
8637290 - 财政年份:2014
- 资助金额:
$ 5.65万 - 项目类别:
Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA
食欲素和瘦素对 VTA 中进食和成瘾行为的调节
- 批准号:
8236865 - 财政年份:2011
- 资助金额:
$ 5.65万 - 项目类别:
Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA
食欲素和瘦素对 VTA 中进食和成瘾行为的调节
- 批准号:
8434870 - 财政年份:2011
- 资助金额:
$ 5.65万 - 项目类别:
Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA
食欲素和瘦素对 VTA 中进食和成瘾行为的调节
- 批准号:
8215386 - 财政年份:2011
- 资助金额:
$ 5.65万 - 项目类别:
Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA
食欲素和瘦素对 VTA 中进食和成瘾行为的调节
- 批准号:
7739920 - 财政年份:2009
- 资助金额:
$ 5.65万 - 项目类别:
CBP Acetyltransferase Function in Addictive Behavior
CBP 乙酰转移酶在成瘾行为中的作用
- 批准号:
7173929 - 财政年份:2006
- 资助金额:
$ 5.65万 - 项目类别:
CBP Acetyltransferase Function in Addictive Behavior
CBP 乙酰转移酶在成瘾行为中的作用
- 批准号:
7290942 - 财政年份:2006
- 资助金额:
$ 5.65万 - 项目类别: