Medicinal Chemistry of Drugs Affecting the Nervous System

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Title
Copyright
End User License Agreement
Contents
Preface
List of Contributors
Drugs Affecting the Cholinergic System
Cory R. Theberge1, Kim Lindsey-Goodrich2 and Ashok E. Philip3,*
HISTORICAL PERSPECTIVES
INTRODUCTORY CONCEPTS
Choline and Acetylcholine
Acetylcholine and Neurotransmission
Cholinergic Neurochemistry: ACh Biosynthesis, Storage, Release, and Metabolism
Cholinergic Receptors - Muscarinic and Nicotinic Subtypes
Clinical Use of Acetylcholine
MUSCARINIC RECEPTOR AGONISTS
MUSCARINIC RECEPTOR ANTAGONISTS (ANTICHOLINERGICS)
Acetylcholinesterase (AChE) Inhibitors
Reversible Noncovalent Inhibitors
Reversible Covalent Inhibitors
Irreversible Covalent Inhibitors
NEUROMUSCULAR BLOCKING AGENTS
Depolarizing Muscle Nicotinic Receptor Neuromuscular Blocking Agents
Non-depolarizing Muscle Nicotinic Receptor Neuromuscular Blocking Agents
Ganglionic-Nicotinic Receptor Blocking Agents
TREATMENT OF ALZHEIMER’S DISEASE (AD)
Epidemiology
Pathophysiology
β-Amyloid Hypothesis
Cholinergic Hypothesis
Other Hypothesis
Pharmacotherapy
Acetyl Cholinesterase (AChE) Inhibitors
Donepezil (Aricept®)
Pharmacokinetics
Side effects/Drug Interactions
Rivastigmine (Exelon®) 2000, Oral; 2008, Patch
Pharmacokinetics
Side effects/Drug Interactions
Galantamine (Razadyne®) 2001
Pharmacokinetics
Side effects/Drug-interactions
NMDA Receptor Antagonist: Memantine (Namenda®) 2003
Pharmacokinetics
Side effects/Drug interactions
Place in Therapy
CASE STUDY
What therapeutic modifications would you make at this time and why?
Drug Discovery Case Study
The Quaternary Advantage – Ipratropium and the Kinetic Selectivity of Tiotropium
STUDENT SELF STUDY GUIDE
PRACTICE QUESTIONS
NOTES
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Drugs Affecting Adrenergic System
M. O. Faruk1,* and Les Ramos2
HISTORICAL BACKGROUND
THE INTRODUCTORY CONCEPTS
Adrenergic Neurotransmitters
Adrenergic Receptors (ARs)
DRUGS AFFECTING ADRENERGIC SYSTEM: STRUCTURES, ACTIVITY, METABOLISM AND RELATED THERAPEUTIC CONSIDERATIONS
The Antiadrenergics Affecting Synthesis, Storage, or Release of NE (Fig. 7)
Metyrosine
Reserpine
Mechanism of Action
Pharmacokinetics
Guanethidine and Guanadrel
Direct-Acting Sympathomimetic Agents
The General Mechanism and SAR of β-Phenylethylamine Derivatives (Direct and Indirect Acting Agonists)
Sar 1
Sar 2
Sar 3
Sar 4
Sar 5
Sar 6
Sar 7
Sar 8
Sar 9
Therapeutic Evaluation of the β-Phenylethylamine Direct Acting Adrenergic Agonists
β2 Adrenergic Agonist and Cardiac Function
Long Acting β2-Adrenoceptor Agonists (LABAs)
β3 Adrenergic Receptor Agonist
The General SAR of Imidazolines (α Adrenergic Agonist and Antagonists)
Sar 1
Sar 2
Sar 3
Therapeutic Evaluation of the Imidazoline α Adrenergic Agonists
Indirect-Acting Sympathomimetics (Figs. 2 and 18)
Adrenergic Receptor Antagonists
The α Adrenergic Antagonists
β-Adrenergic Receptor Antagonists (β-Blockers)
Sar 1
Sar 2
Sar 3
Sar 4
Sar 5
Nonselective β-Blockers
Selective β1-Blockers (Cardioselective β-Blockers)
Black Box Warning with Systemic Use β-Blockers
CASE STUDIES
DRUG DISCOVERY CASE STUDIES
Discovery of Adrenergic Agonists [48]
Discovery of Adrenergic Antagonists – The Discovery of Propranolol [49]
STUDENT SELF-STUDY GUIDE
STUDENT SELF-ASSESSMENT QUESTIONS
The duration of action of X,Y,Z is in the order (longest to shortest)
REFERENCES
Phenothiazines and Related Antipsychotic Drugs
Mamoon Rashid1, Mehbuba Rahman1 and M. O. Faruk Khan2,*
HISTORICAL BACKGROUNDS
INTRODUCTORY CONCEPTS
Psychotic Disorders and Relevant Terminologies
Dopamine Hypothesis of Psychosis and Site of Action of Antipsychotics
Schizophrenia-associated Neurotransmitters and Circuitry in the Brain
Evidence Against the Hypothesis
The Dopaminergic Neurons, Synthesis, and Degradation of Dopamine
Receptors of Dopamine
The Interaction of Dopamine Receptor and Antipsychotic Agents
Other Receptors Involved in Antipsychotic Drug Action
THE ANTIPSYCHOTIC DRUGS
Classes of Antipsychotic Drugs
First Generation (Typical) Antipsychotic Drugs
Potency Comparison of Piperazine, Aliphatic and Piperidine Type Antipsychotic Agents
Butyrophenone Antipsychotics and Related SAR
SECOND GENERATION (ATYPICAL) ANTIPSYCHOTICS
General Mechanisms of Action and Side Effects
Selected Clinically Used Second-Generation Antipsychotics
Clozapine and Olanzapine
Quetiapine
Asenapine
Cariprazine
Risperidone Paliperidone and Ziprasidone
Lurasidone
Iloperidone
Aripiprazole
Brexpiprazole
Selected Antipsychotic Drugs and Their Interaction with Dopamine and other Receptors
CASE STUDIES
Clinically Relevant Case Studies
DRUG DISCOVERY CASE STUDIES
Discovery of Haloperidol
Discovery of Ziprasidone
STUDENT SELF-STUDY GUIDE
STUDENTS SELF-ASSESSMENT QUESTIONS
NOTES
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Antidepressant Drugs
Horrick Sharma1, Michaela Leffler2 and M. O. Faruk Khan3,*
HISTORICAL PERSPECTIVE
INTRODUCTORY CONCEPTS
Affective Disorders
Pathophysiology - Biogenic Amine Hypothesis
Classification of Antidepressants
Consequence of Ring Geometry of TCA
SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)
Tricyclic Antidepressants (TCAs)
Mechanism of Action
Adverse Effects
General SAR of TCAs
Ring Substitutions
γ-Nitrogen Substituents
INDIVIDUAL CLINICALLY USED TCAS
Imipramine (TofranilTM)
Clomipramine (AnafranilTM)
Amitriptyline
Protriptyline (VivactilTM)
Trimipramine (SurmontilTM)
Doxepin (PrudoxinTM)
Maprotiline (LudiomilTM)
Amoxapine (AsendinTM)
PHENYLALKYLAMINE SNRIS
Venlafaxine (EffexorTM)
Milnacipran (SavellaTM)
Duloxetine (CymbaltaTM)
SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITOR (NRIS)
Phenoxyphenylpropylamines (Fig. 14)
Mechanism of Action
Adverse Effects
Atomoxetine (StratteraTM)
Reboxetine (EdronaxTM)
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)
Mechanism of Action
Adverse Effects
Phenoxyphenylalkylamines
SAR of Phenoxyphenylalkylamines
Fluoxetine (ProzacTM)
Disorder (OCD)
Paroxetine (PaxilTM)
Citalopram (CelexaTM)
Phenylalkylamines
Sertraline (ZoloftTM)
Fluvoxamine (LuvoxTM)
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Mechanism of Action
Adverse Effects
Phenelzine and Tranylcypromine
MISCELLANEOUS AGENTS
Trazodone (DesyrelTM)
Mirtazapine (RemeronTM)
Bupropion (WellbutrinTM)
CASE STUDIES
Case 1
Case 2
Case 3
DRUG DISCOVERY CASE STUDY
Discovery of SSRIs and Fluoxetine
STUDENT SELF STUDY GUIDE
STUDENTS SELF-ASSESSMENT QUESTIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Sedatives, Hypnotics and Anxiolytics
Donald Sikazwe*
HISTORICAL BACKGROUND
INTRODUCTORY CONCEPTS
Sedative-hypnotics
Anxiolytics
Mechanisms of Action
γ-Amino Butyric Acid (GABA) Receptor Modulation
Melatonin MT1/MT2 Receptor Activation
5-HT1A Receptor Activation
BARBITURATES
Individual Barbiturate Drugs (Mechanism, Metabolism, Drug Interactions)
Long Acting Barbiturates (DOA> 6 h)
Intermediate Acting Barbiturates (DOA 3-6h)
Short Acting Barbiturates (DOA< 3 h)
Barbiturate SAR
BENZODIAZEPINES
Individual Benzodiazepine Drugs (Mechanisms, Metabolism, and Drug Interactions)
Long-acting BZDS (t1/2 >24 hours)
Quazepam (Doral) [10, 39, 53]
Intermediate Acting BZDs (t1/2 5-24 Hours)
Short-acting BZDS (t1/2 < 5 Hours)
Benzodiazepine SAR
NON-BENZODIAZEPINES
Individual Non-benzodiazepine Drugs (Mechanisms, Metabolism, Drug Interactions)
Zolpidem Tartrate (Ambien®) [5, 8, 10, 51, 61]
Zaleplon (Sonata®) [5, 8, 10, 51, 62]
Eszopiclone (Lunesta®) [5, 8, 10, 51]
Meprobamate (Equanil) [2, 57, 59]
Ramelteon (Rozerem®) [10, 51, 63 - 65]
Buspirone (Buspar®) [6, 31, 51]
Suvorexant (Belsomra®) [70]
Lemborexant (Dayvigo®) [71]
CASE STUDIES
Case 1
Case 2
Case 3
DRUG DISCOVERY CASE STUDIES
Case 1: Meprobamate Discovery [3]
Case 2: Chlordiazepoxide/Diazepam Discovery [3, 4, 66]
Case 3: Ramelteon Discovery [65, 67, 68]
STUDENT SELF-STUDY GUIDE
STUDENT SELF-ASSESSMENT QUESTIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Antiepileptic Drugs
Tamer E. Fandy1, Michaela Leffler2 and M. O. Faruk Khan3,*
HISTORICAL PERSPECTIVE
INTRODUCTORY CONCEPTS
Terminology
Pathophysiology of Epilepsy and Seizure
Intrinsic and Extrinsic Ionic Factors Modifying Neuronal Excitability [4]
Glutamate and GABA Biosynthesis and Metabolism
ANTIEPILEPTIC DRUGS IN CLINICAL PRACTICE
MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
CHEMISTRY OF ANTIEPILEPTIC DRUGS
Pharmacophore for Antiepileptic Drugs
Chemical Classes of Antiepileptics Drugs
General Structure Activity Relationship
INDIVIDUAL ANTIEPILEPTIC DRUGS
Barbiturates and Related Drugs
SAR of Barbiturates
Phenobarbital and Primidone
Hydantoins
SAR OF HYDANTOINS
INDIVIDUAL DRUGS
Phenytoin
Fosphenytoin
Ethotoin
Oxazolidinediones
Drugs
Succinimides
Ethosuximide and Methsuximide
Benzodiazepines
Dibenzazepines
Carbamazepine (Tegretol®, Others)
Oxcarbazepine (Trileptal®)
MISCELLANEOUS ANTIEPILEPTICS
Eslicarbazepine Acetate (Aptiom®)
Valproic Acid/Valproate
Felbamate (Felbatol)
Gabapentin (Neurontin), Pregabalin (Lyrica) and Gabapentin Enacarbil (Horizant) [43]
Levetiracetam (Keppra) and Brivaracetam (Briviact®)
Vigabatrin (Sabril) [48]
Lamotrigine (Lamictal®)
Tiagabine (Gabitril®)
Topiramate (Topamax®)
Zonisamide (Zonegran®)
Lacosamide (Vimpat®)
Rufinamide (Banzel®)
Ezogabine (Potiga®)
Perampanel (Fycompa®)
Cannabidiol (Epidiolex)
ANTIEPILEPTICS IN PEDIATRICS
THERAPEUTIC DRUG MONITORING IN ANTIEPILEPTIC DRUGS
COMPARATIVE SAFETY OF ANTIEPILEPTIC DRUGS DURING PREGNANCY
CASE STUDIES
Case 1
Questions
Case 2
Questions
Case 3
Questions
DRUG DISCOVERY CASE STUDIES
Discovery of Beclofen and Other GABA Analogues
Discovery of Brivaracetam
STUDENT SELF-STUDY GUIDE
STUDENT SELF-ASSESSMENT QUESTIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
General and Local Anesthetic Agents
Carolyn J. Friel*
HISTORICAL BACKGROUND
INTRODUCTORY CONCEPTS
Mechanism of Action of General Anesthetics
Mechanism of Action of Local Anesthetics
CLASSES OF GENERAL ANESTHETICS AND THEIR DISCUSSION
The Injectable General Anesthetics
Adjuvant drugs used in General Anesthesia
The Inhaled General Anesthetics
CLASSES OF LOCAL ANESTHETICS AND THEIR DISCUSSION
Ester Group Local Anesthetics
Amide Type Local Anesthetics
CASE STUDIES
DRUG DISCOVERY CASE STUDIES
General Anesthetics: The development of Halothane
Amide Class Local Anesthetics: The Development of Ropivacaine
STUDENTS SELF-ASSESSMENT QUESTIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Parkinson Disease and Antiparkinsonian Drugs
Ashok E. Philip1,*, George DeMaagd2 and M. O. Faruk Khan3
HISTORICAL BACKGROUND
INTRODUCTORY CONCEPTS
Clinical Overview, Etiology and Risk Factors
MPTP-Induced Neuronal Cell Death
Oxidative Stress
Environmental Toxins
Genetic Association
Dopamine: Biosynthesis, Metabolism and Receptor Function
DA Biosynthesis and Metabolism
DA Receptors and Function
Dopaminergic Pathways
Pathophysiology
Drug Induced Movement Disorders
PHARMACOLOGICAL AND NON-PHARMACOLOGICAL MANAGEMENT OF PARKINSON DISEASE (PD)
Pharmacological Management of Parkinson Disease (PD)
Levodopa (L-DOPA)
Mechanism of Action
Pharmacokinetics [99, 134, 138, 139]
Metabolism and Carbidopa
Adverse Effects
Motor Complications of L-DOPA
“Wearing Off”
“On/Off Phenomenon”
Dyskinesias
Dystonias
Drug Interactions [164]
Contraindications and Precautions
Dopamine Receptor Agonists
Ergot Class
Non-Ergot Class
Mechanism of Action
Rotigotine Transdermal Patch (Neupro®)
Apomorphine (Apokyn®)
Adverse Effects
Drug Interactions
Contraindications and Precautions
Catechol-O-methyltransferase (COMT) Inhibitors
Mechanism of Action
Tolcapone (Tasmar ®)
Entacapone(Comtan ®)
Selective MAO-B Inhibitors
Mechanism of Action
Selegiline (Eldepryl® and Zelapar® ODT)
Rasagiline (Azilect®)
Adverse Effects
Drug Interactions and Contraindications
Safinamide (Xadago®)
Anticholinergic Agents
Amantadine
Mechanism of Action
Adenosine Receptor Antagonist
CASE STUDIES
Case 1
Case 2
DRUG DISCOVERY CASE STORY
Discovery of Pramipexole
STUDENT SELF-STUDY GUIDE
STUDENT SELF-ASSESSMENT QUESTIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Subject Index
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