Medicinal Chemistry of Drugs Affecting the Nervous System

Table of Contents

Chapter 1 Drugs Affecting the Cholinergic System

• 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
• Cory R. Theberge, Kim Lindsey-Goodrich and Ashok E. Philip
• Notes
• Consent for Publication
• Conflict of Interest
• Acknowledgements
• References

Chapter 2 Drugs Affecting Adrenergic System

• 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
• 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
• 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
• M. O. Faruk and Les Ramos
• Selective Β1-Blockers (Cardioselective Β-Blockers)
• Black Box Warning with Systemic Use Β-Blockers
• Case Studies
• Drug Discovery Case Studies
• Discovery of Adrenergic Agonists
• Discovery of Adrenergic Antagonists - the Discovery of Propranolol
• Student Self-Study Guide
• Student Self-Assessment Questions
• The Duration of Action of X,Y,Z is in the Order (Longest to Shortest)
• References

Chapter 3 Phenothiazines and Related Antipsychotic Drugs

• 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
• Mamoon Rashid, Mehbuba Rahman and M. O. Faruk Khan
• Conflict of Interest
• Acknowledgements
• References

Chapter 4 Antidepressant Drugs

• 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
• 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)
• Horrick Sharma, Michaela Leffler and M. O. Faruk Khan
• 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

Chapter 5 Sedatives, Hypnotics and Anxiolytics

• 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)
• 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®)
• Zaleplon (Sonata®)
• Eszopiclone (Lunesta®)
• Meprobamate (Equanil)
• Ramelteon (Rozerem®)
• Buspirone (Buspar®)

Samples

Author

• Ashok E. Philip
• M. O. Faruk Khan