Synthesis and in vitro and in vivo screening of fused and tethered heterocyclic peptidomimetics for the discovery of new analgesics with decreased side effects
Synthesis and in vitro and in vivo screening of fused and tethered heterocyclic peptidomimetics for the discovery of new analgesics with decreased side effects
批准号:
10297832
负责人:
Jay P. McLaughlin
金额:
$29.71万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-04-11 至 2024-11-30
关键词:
Absence of pain sensationAcetic AcidsAddressAffinityAgonistAmino AcidsAnalgesicsAreaBCL2L11 geneBehavior assessmentBindingBinding ProteinsBiologicalBiological AssayBiological AvailabilityBloodBlood - brain barrier anatomyBrainClinicalConstipationCyclic AMPDataDevelopmentDoseDrug KineticsEvaluationExhibitsFailureGenerationsGoalsHarvestHeterocyclic CompoundsImidazolidinesIminesIn VitroLeadLead levelsLibrariesLiverMass Spectrum AnalysisMeasurementMediatingMetabolicMolecular ProbesMorphineMotor ActivityMusNaloxoneOpiate AddictionOpioidOpioid AnalgesicsOpioid AntagonistOpioid ReceptorOpioid agonistOralOral AdministrationOutcomePainParentsPeptidesPeripheralPermeabilityPhysiologicalPiperazinesPlasma ProteinsPropertyResearchRewardsSedation procedureSeriesSideSignal TransductionSuggestionSystemTailTestingTimeVentilatory DepressionVertebral columnWaterWithdrawalabuse liabilityantagonistaqueousbasebeta-arrestincomputational chemistryconditioned place preferencedesigngastrointestinal epitheliumimidazoloneimprovedin vivoinnovationinterestintravenous administrationkappa opioid receptorsliquid chromatography mass spectrometrynovelpeptidomimeticsradioligandreceptorrecruitrespiratoryscaffoldscreeningside effectsmall moleculetherapeutic opioid
中文摘要
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英文摘要
We hypothesize that the development of peripherally-restricted, mixed-activity opioid receptor agonists will
produce robust analgesia while exhibiting reduced side effects, including a lack of respiratory depression or
reinforcing properties. In preliminary studies, the in vitro screening of novel bis-imidazolidines and fused
heterocyclic lead compounds BIM-22 and FDC-14 identified mixed-opioid receptor agonist activity. After
peripheral (i.p.) administration to mice, both compounds demonstrated antinociception equivalent to morphine
in the 55oC warm-water tail withdrawal (tail-flick) assay, but FDC-14 was 25 times more potent than morphine
in the acetic acid writhing test, with an antinociceptive potency ratio of 72.7, suggestive of peripherally-
restricted activity. Confirming this, LC-MS/MS studies detected BIM-22 and FDC-14 in harvested mouse blood,
but not brain, after i.v. administration. This proposal addresses two research areas of particular interest for this
FOA: i) The development of new and innovative molecular probes for receptors and new strategies for
innovative peptidomimetic design, and ii) The identification of structurally diverse, orally active, metabolically
stable peripherally-restricted opioid agonists. We propose six interacting aims: In Aim 1, we propose the
computationally guided synthesis of heterocyclic peptidomimetics: bis-imidazolidin-2-imines, piperazines, bis-
piperazine, bis-imidazolone and fused heterocyclic libraries. In Aim 2, we will screen all compounds in
competition radioligand binding assays to determine affinity for μ- (MOR), δ- (DOR), and κ- (KOR) opioid
receptors, and in functional assays to identify dual δ/κ or dual δ/µ agonists. In Aim 3, ten selected compounds
will be evaluated in vitro for pharmacokinetic properties and screened in vivo for antinociception using the
mouse tail-flick assay. Lead compounds identified from this aim will guide 2nd generation SAR studies to
enhance peripherally-selective activity. In Aim 4: we will perform full in vivo antinociceptive characterization of
lead agonist compounds. The most stable, active 4 agonists not crossing the BBB in Aims 2+3 will be
evaluated after i.p. administration with mouse tail-flick and acetic-acid writhing assays for efficacy, duration of
action, and opioid receptor selectivity. In Aim 5: we will characterize the bioavailability in mice of the selected 4
agonists following oral administration and confirm their inability to penetrate the blood brain barrier. In Aim 6:
The two most potent bioavailable novel agonists identified in Aims 1-5 will be examined for liabilities,
specifically antinociceptive tolerance, respiratory and hyperlocomotor effects in the CLAMS physiological and
behavioral assessment system, sedation and disruption of coordinated locomotor activity in the rotorod assay,
and assessment for rewarding or aversive effects in the conditioned place preference (CPP) assay. Effects on
GI transit will also be evaluated to assess effects on constipation. In summary, we expect to generate novel
peripherally-restricted, mixed-activity peptidomimetic opioid receptor agonists as both probes and analgesics
with reduced side effects, thereby significantly impacting analgesic development.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/ijms23179623
发表时间:
2022-08-25
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[]
通讯作者:
Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine
-
批准号:10089427
-
项目类别:
-
资助金额:$51.56万
-
财政年份:2013
-
负责人:Jay P. McLaughlin
-
依托单位:
Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine
-
批准号:10343679
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项目类别:
-
资助金额:$51.52万
-
财政年份:2013
-
负责人:Jay P. McLaughlin
-
依托单位:
Tat mediation of HIV-associated mood disorders via functional deficits in brain
-
批准号:8287532
-
项目类别:
-
资助金额:$42.72万
-
财政年份:2011
-
负责人:Jay P. McLaughlin
-
依托单位:
Tat mediation of HIV-associated mood disorders via functional deficits in brain
-
批准号:8830474
-
项目类别:
-
资助金额:$36.06万
-
财政年份:2011
-
负责人:Jay P. McLaughlin
-
依托单位:
Tat mediation of HIV-associated mood disorders via functional deficits in brain
-
批准号:8658705
-
项目类别:
-
资助金额:$42.44万
-
财政年份:2011
-
负责人:Jay P. McLaughlin
-
依托单位:
Tat mediation of HIV-associated mood disorders via functional deficits in brain
-
批准号:8452691
-
项目类别:
-
资助金额:$40.79万
-
财政年份:2011
-
负责人:Jay P. McLaughlin
-
依托单位:
Tat mediation of HIV-associated mood disorders via functional deficits in brain
-
批准号:8140834
-
项目类别:
-
资助金额:$45.48万
-
财政年份:2011
-
负责人:Jay P. McLaughlin
-
依托单位:
Endogenous Opioid Mechanisms Modulating Stress
-
批准号:7274393
-
项目类别:
-
资助金额:$0.91万
-
财政年份:2004
-
负责人:Jay P. McLaughlin
-
依托单位:
Endogenous Opioid Mechanisms Modulating Stress
-
批准号:6723870
-
项目类别:
-
资助金额:$7.86万
-
财政年份:2004
-
负责人:Jay P. McLaughlin
-
依托单位:
Endogenous Opioid Mechanisms Modulating Stress
-
批准号:6946363
-
项目类别:
-
资助金额:$7.85万
-
财政年份:2004
-
负责人:Jay P. McLaughlin
-
依托单位:
Endogenous Opioid Mediation of Stress and Drug Reward
-
批准号:6673075
-
项目类别:
-
资助金额:$7.58万
-
财政年份:2003
-
负责人:Jay P. McLaughlin
-
依托单位:
海外基金