Drug Discovery for the Treatment of Addiction : Medicinal Chemistry Strategies

360 Pages·2014·10.79 MB·English

by  Brian S. Fulton

Drug Discovery
for the Treatment
of Addiction
Medicinal Chemistry Strategies
Brian S. Fulton

DRUG DISCOVERY FOR
THE TREATMENT OF
ADDICTION

DRUG DISCOVERY FOR
THE TREATMENT OF
ADDICTION
Medicinal Chemistry Strategies
BRIANS.FULTON
VisitingLecturer
DepartmentofChemistryandChemicalBiology
NortheasternUniversity
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Fulton,BrianS.,author.
Drugdiscoveryforthetreatmentofaddiction:medicinalchemistrystrategies/BrianS.Fulton.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-61416-7(cloth)
I.Title.
[DNLM:1.Substance-RelatedDisorders–drugtherapy. 2.DrugDiscovery. 3.Neurotransmitter
Agents. WM270]
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CONTENTS
Preface xiii
1 WhatIsDrugAddiction? 1
1.1 Definitions, 2
1.2 TheDrugsofAbuse, 4
1.3 ScheduleofControlledSubstances, 5
1.3.1 ScheduleIControlledSubstances, 5
1.3.2 ScheduleIIControlledSubstances, 5
1.3.3 ScheduleIIIControlledSubstances, 6
1.3.4 ScheduleIVControlledSubstances, 6
1.3.5 ScheduleVControlledSubstances, 6
1.4 SomeFactsFrom2012NSDUHStudy, 6
1.5 TheAddictiveState, 8
1.5.1 StagesofAddiction, 9
1.6 TheoriesofAddiction, 12
1.7 Comorbidity, 13
1.8 GeneticAspectsofAddiction, 13
1.9 ApprovedMedicationsfortheTreatmentofSubstanceAbuse
andAddiction, 16
2 PhysiologicalBasisofAddiction—AChemist’sInterpretation 18
2.1 TheRewardSystem, 19
2.2 NeuroanatomyoftheRewardSystem, 21
2.3 BriefReviewoftheCentralNervousSystemandAddiction, 22
2.3.1 NeuronFiring, 24
vii
viii CONTENTS
2.4 NeurotransmittersandTheirTargets, 25
2.4.1 Neurotransmitters, 25
2.4.2 Receptors, 27
2.4.3 G-Protein-CoupledReceptors, 28
2.4.4 IonChannels, 30
2.4.5 G-Protein-ActivatedInwardlyRectifyingK+Channels, 31
2.4.6 Transporters, 32
2.5 NeurocircuitryandNeurotransmittersinAddiction, 32
2.5.1 GlutaminergicSysteminDrugAddiction, 33
2.5.2 GABAergicSysteminDrugAddiction, 39
2.5.3 CholinergicSysteminDrugAddiction, 42
2.5.4 DopaminergicSysteminDrugAddiction, 46
2.5.5 AdrenergicSysteminDrugAddiction, 50
2.5.6 SerotonergicSysteminDrugAddiction, 51
2.5.7 VesicularMonoamineTransporters, 55
2.5.8 CannabinoidSysteminDrugAddiction, 56
2.5.9 OpioidSysteminDrugAddiction, 58
2.6 LocationofReceptors, 62
2.7 AnExample, 64
2.8 UseofBiologicalMarkers, 65
2.8.1 AlcoholUseBiomarkers, 66
2.8.2 MethamphetamineUseBiomarkers, 67
2.9 MemoriesandAddiction, 68
2.10 Stress,theHPAAxis,andAddiction, 72
3 BehavioralPharmacologyandAddiction 76
3.1 AnimalModelsofAddiction, 76
3.2 Self-Administration, 80
3.2.1 ChronicIntravenousDrugSelf-AdministrationinRats
andMice, 80
3.2.2 IntravenousSelf-AdministrationTechniquesinMonkeys, 84
3.3 ConditionedPlacePreference, 85
3.4 Tolerance, 86
3.5 Extinction/Withdrawal, 87
3.6 Reinstatement(AnimalModelsofRelapse), 87
3.7 DrugDiscrimination, 89
3.8 OperantSensationSeekingModel, 92
3.9 UseofAnimalBehavioralModels, 92
Acknowledgments, 93
4 MedicationDevelopmentfortheTreatmentofDrugAddiction 94
4.1 LeadDiscovery, 95
4.1.1 NIDAAddictionTreatmentDiscoveryProgram, 96
4.2 PharmacologicalAssays, 103