2_MedChem_of_CNS_depressants

Page 1: Medicinal Chemistry of CNS Depressants

• Course Title: Medicinal Chemistry of CNS Depressants – Part 1

• Instructor: Dr. Ahmed Elkerdawy

• Position: Senior Lecturer in Pharmaceutical Chemistry

• Contact: aelkerdawy@lincoln.ac.uk

• Location: JBL2W25

Page 2: Reading List

• Wilson and Gisvold's Textbook

  • Authors: Block, John H.; Wilson, Charles Owens; Beale, John Marlowe

  • 12th edition, International

  • Published by Wolters Kluwer/Lippincott Williams & Wilkins in 2011

  • ISBN: 1609133986, 9781609133986

  • Relevant Chapters: 12 & 14

• Foyes Principles of Medicinal Chemistry

  • Editors: Lemke, Thomas L.; Zito, William S.; Roche, Victoria F.; Williams, David A.

  • Eighth, International Edition

  • Published by Wolters Kluwer Health in 2020

  • ISBN: 1975139038, 9781975139032

  • Relevant Chapters: 14-17

Page 3: CNS Depressants

• Categories of CNS Depressants:

  1. Anti-psychotics

  2. Sedative, hypnotic, and anxiolytic agents

  3. Anti-epileptics

Page 4: Anti-psychotics Overview

• Anti-psychotics (Neuroleptics, Major Tranquilizers)

  • Discussed in detail by Dr. Ahmed Elkerdawy

• Focus Area: Chemical structure and pharmacology

Page 5: Anti-psychotics Definition

• Anti-psychotics

  • Categories include Neuroleptics and Major Tranquilizers

Page 6: Anti-psychotics Uses

• Primary Uses:

  • Treat psychosis and schizophrenia

  • Act as anti-emetic due to D2-blocking properties at the CTZ (Chemoreceptor Trigger Zone)

Page 7: Symptoms in Schizophrenia

• Schizophrenia Symptoms:

  • Positive Symptoms: Delusions, Hallucinations

  • Negative Symptoms: Blunted affect, Apathy

  • Mechanism: Involves hyperactivity of mesolimbic D2 and 5-HT2A receptors

• Anti-psychotic Types:

  • Typical (Strong D2 antagonists)

  • Atypical (Weaker D2 antagonists, Less EPS)

Page 8: Dopaminergic Pathways

• Dopamine Pathways in the Brain:

  • Nigrostriatal Pathway: Movement control

  • Mesolimbic Pathway: Reward and emotion

  • Mesocortical Pathway: Cognitive function

  • Tuberoinfundibular Pathway: Hormonal regulation

  • Reference: Stahl, S. M. (2013). Stahl's Essential Psychopharmacology.

Page 9: Classifications of Anti-psychotics

• Typical Anti-psychotics (First Generation):

  1. Phenothiazines

  2. Thioxanthenes

  3. Butyrophenones

  4. Diphenylbutylpiperidines

• Mechanism: Block D2 receptors → Increased EPS (Extra-pyramidal symptoms)

Page 10: Side Effects of Anti-psychotics

• Typical Side Effects:

  • Extra-pyramidal symptoms (EPS) → resembling Parkinsonism

  • Anti-cholinergic effects: Dry mouth, blurred vision

  • Sedation due to central H1-blocking

  • Hypotension due to peripheral α1-blocking

  • Other: Photosensitivity, retinal toxicity

Page 11: Phenothiazines Structure

• Phenothiazines Overview:

  • Main Structure: Tricyclic base (6-6-6 system)

  • Variation in alkyl substitutions leads to differing potencies and side effects

Page 12: Chlorpromazine (Phenothiazines)

• Chlorpromazine (CPZ):

  • Prototype of phenothiazines

  • Side Effects: Sedation and hypotension due to H1 and α1 blockage

Page 13: Binding Conformation of Phenothiazines

• Binding Mode:

  • Similar to Dopamine (DA) in D2 receptor binding, utilizing trans α-rotamer conformation

Page 14: Structure-Activity Relationship (SAR)

• Position 2 Substitution:

  • Electron-withdrawing Groups (EWGs such as Cl, CF3) enhance activity through hydrogen bonding

  • Arrangement mimics dopamine

Page 15: SAR Influences at Positions 1 and 4

• Position 1 Substitution:

  • Disturbs DA-like conformation → decreases activity

• Position 4 Substitution:

  • Disrupts binding to D2 receptors → decreases activity

Page 16: C-Chain SAR in Phenothiazines

• C-Chain Structure:

  • 3 carbon atoms optimal for activity; modifications reduce effectiveness

  • Branching at β-position diminishes activity

Page 17: Amine SAR in Phenothiazines

• Amine Group:

  • Tertiary amine structure is optimal for activity

  • N-dealkylation reduces activity, while cyclic N retains activity

Page 18: Additional SAR Considerations

• Further Influences:

  • EWGs at R2 → increase in activity

  • Optimal activity seen in tertiary amines

  • C-chain optimal at 3 carbons

Page 19: Classes of Phenothiazines

• Phenothiazine Classes:

  • Propyl Dialkylamino derivatives

  • Alkyl Piperidyl derivatives

  • Piperazinyl derivatives

Page 20: Examples of Propyl Dialkylamino Derivatives

• Examples:

  • Promazine, Chlorpromazine, and Triflupromazine

  • Notable for increased EPS and anti-psychotic potency

Page 21: Metabolism of Anti-psychotics

• Metabolic Pathways:

  • N-dealkylation and C7 Hydroxylation lead to increase side effects

  • Key metabolic transformations observed in phenothiazines

Page 22: Thioridazine and Mesoridazine

• Effects:

  • High anticholinergic effects reduce EPS risk

  • Associated with cardiotoxicity and pigmentary retinopathy

  • Use discontinued due to severe toxicity profiles

Page 23: Alkyl Piperidyl Derivatives

• Example: Pericyazine

  • Notably short-acting (t1/2 = 12hr) due to rapid metabolism

Page 24: Propyl Piperazinyl Derivatives

• Examples:

  • Prochlorperazine, Trifluoperazine, Fluphenazine

  • Notorious for high activity and EPS side effects

Page 25: Thioxanthenes Overview

• Thioxanthenes Properties:

  • Similar pharmacology to Phenothiazines

  • Short duration, potential strategies for prolonging effects

Page 26: Butyrophenones Structure

• Main Nucleus:

  • Overview of structure and its implications on activity

Page 27: Butyrophenones Properties

• Examples: Haloperidol and Benperidol

  • Increased potency with EPS side effects

  • Noted for their short duration of action

Page 28: Diphenylbutylpiperidines Overview

• Example: Pimozide

  • Notable for its long duration of action and lipophilicity

Page 29: Atypical Anti-psychotics Overview

• Atypical Agents:

  • Primarily act on D2 and 5HT2A receptors, less EPS than typical agents

  • Effective in alleviating negative symptoms of schizophrenia

Page 30: Atypical Anti-psychotics Structure

• Compounds:

  • Includes Dibenzodiazepines, Dibenzoxazepines, Thienobenzodiazepines

• Examples: Clozapine, Loxapine, Olanzapine

Page 31: Amisulpride Mechanism

• Mechanism of Action:

  • Important for H-bonding for antipsychotic activity in this category

Page 32: Benzamides Overview

• Compounds: Includes agents like Risperidone and Paliperidone

  • Similar effects as typical but with less EPS

Page 33: Aripiprazole Properties

• Aripiprazole Mechanism:

  • Partial agonist at D2 receptors, significant duration of action

  • Active metabolites contribute to prolonged effects

Page 34: Summary of CNS Depressants

• CNS Depressants: Summary of categories - Anti-psychotics

  • Atypical and Typical classifications discussed

Page 35: Medicinal Chemistry of CNS Depressants – Part 2

• Continuation of lectures by: Dr. Ahmed Elkerdawy

Page 36: CNS Depressants Recap

• Discussion on categories:

  1. Sedative, Hypnotic, and Anxiolytic Agents

  2. Anti-epileptics

  3. Anti-psychotics

Page 37: Sedative, Hypnotic, and Anxiolytic Agents

• Overview of Sedation Levels:

  • Dose-dependent effects ranging from mild sedation to coma and death

Page 38: Neurotransmitter Structures

• Key Neurotransmitters: GABA, Glycine, -Aminobutyric Acid

  • GABA receptors (GABAA & GABAB) are crucial for inhibitory neurotransmission

Page 39: GABAA Receptor Function

• Functionality:

  • Ligand-gated chloride ion channel, mediating hyperpolarization

Page 40: Allosteric Regulation of GABAA

• Allosteric Regulation:

  • Enhancers increase activity while inhibitors decrease it

Page 41: Actions of Sedative Agents

• Dosing Effects:

  • Lowest dose → sedation; highest dose → coma, possible death

Page 42: Pharmacokinetics of Sedatives

• Key Pharmacokinetic Properties:

  1. High lipophilicity leads to rapid CNS distribution

  2. Significant placental transfer during pregnancy

  3. Metabolism leads to less active excretion products

Page 43: Classes of Sedative Agents

• Main Classes:

  1. Barbiturates

  2. Benzodiazepines

  3. Non-Benzodiazepines (Z-drugs)

  4. Miscellaneous

Page 44: Barbiturate Mode of Action

• Mechanism:

  • Positive modulation of GABA-linked chloride channel opening

  • Mimics GABA action without requiring its presence

Page 45: Indications for Barbiturates

• Use Cases:

  • Anesthetic, hypnotic, anti-convulsant

  • High potential for habituation and tolerance

Page 46: Barbiturates Structure

• Structural Overview:

  • Highlighting key substructures and their implications on function

Page 47: Barbiturate SAR: Free Acid

• Importance of Free Acid:

  • Essential for activity across compounds

Page 48: SAR: Substitution Effects

• Effect of Substitution:

  • Identifying how molecular changes affect pharmacological efficacy

Page 49: Barbiturate Position 5 Substitutions

• Influences of Position 5:

  • Determine onset and duration through lipophilicity adjustments

Page 50: Barbiturate Classifications

• Classification by Action:

  • Categorized based on duration and onset properties, primarily impacted by lipophilicity

Page 51: Benzodiazepines Overview

• Mechanism of Action for Benzodiazepines:

  • Positive modulation on GABAA receptor leading to hyperpolarization

Page 52: Indications for Benzodiazepines

• Use Cases:

  • Anxiety, insomnia, muscle spasms, anti-convulsant

  • Side effects can include drowsiness, weight gain, and dependence

Page 53: Advantages of Benzodiazepines

• Benzodiazepines vs Barbiturates:

  • Less risk of tolerance and overdose potential, safer profile

Page 54: Benzodiazepine Structure

• Nucleus Overview:

  • Essential structural components identified for activity

Page 55: Benzodiazepine Classes

• Sub-categories of Benzodiazepines:

  • 1,4-Benzodiazepine-4-oxides and 1,2-Annealated types

Page 56: Chlordiazepoxide SAR

• Chlordiazepoxide Highlights:

  • Importance of substituents and their effects on pharmacological activity

Page 57: Lorazepam Properties

• Active and Metabolic Properties:

  • Rapid metabolism leading to shorter duration of action

Page 58: Clorazepate Mechanism

• Prodrug Mechanism:

  • Activated in the body leading to Nordazepam

Page 59: Midazolam and Triazolam

• Short Acting Benzodiazepines:

  • Usage in surgical settings due to fast onset

Page 60: Non-benzodiazepines Overview

• Mechanisms and Benefits:

  • Advantages of non-benzodiazepines in minimizing withdrawal symptoms

Page 61: Miscellaneous Agents Overview

• Characteristics of Buspirone:

  • Mechanism as a presynaptic 5-HT1A partial agonist, reducing 5-HT release

Page 62: Summary of Sedative Agents

• Main Classes Summarization:

  • Barbiturates, Benzodiazepines, Non-benzodiazepines, and Miscellaneous discussed

Page 63: Anticonvulsant Overview

• Focus: Anti-seizure and anti-epileptic drugs overview

Page 64: Types of Seizures

• Classification by Seizures:

  1. Generalized Seizures (Tonic-clonic, Absence)

  2. Partial Seizures

  3. Unilateral Seizures

Page 65: Mechanisms of Anti-epileptic Drugs

• Modulation Mechanisms:

  • Targeting ion channels (Na+, Ca2+, K+) and GABA-mediated transmission

Page 66: Drug Indications by Seizure Type

• Examples of Anti-seizure Drugs:

  • Various classes used for specific seizure types outlined for reference

Page 67: Anticonvulsant Classes Overview

• Main Classes:

  1. Ureides

  2. Benzodiazepines

  3. Carbamazepine and Analogues

  4. Valproic acid

  5. GABA analogues

  6. Novel broad-spectrum anticonvulsants

Page 68: Ureides Properties

• Mechanisms:

  • Pharmacological activity determined by substitution patterns

Page 69: Benzodiazepines Mechanism

• Use in Seizures: Benzodiazepines highlighted for their role in various seizure scenarios

Page 70: Carbamazepine and analogues

• Key Mechanism: Stabilization of inactive Na+ channels identified as a primary action mechanism

Page 71: Valproic Acid Overview

• Broad Spectrum Agent: Utilized widely due to various mechanisms of action

Page 72: GABA Analogues Usage

• Key Agents: Gabapentin, Pregabalin described in detail

Page 73: Novel Broad-spectrum Anticonvulsants

• Examples: Lamotrigine, Topiramate, Levetiracetam

  • Mechanisms cover wide ranges of action across multiple channels and neurotransmitter systems

Page 74: Summary of Anticonvulsants

• Overview of Anti-epileptics: Summarizing different classes and their properties for easy review