Chemical Pharmacology I: Acetylcholine Agonists

Acetylcholine Agonists

• Muscarinic (G-protein coupled) and nicotinic (ligand-gated ion channels) cholinergic receptors are two types of receptors.
• Biosynthesis of acetylcholine involves serine, serine decarboxylase, choline N-methyltransferase, and choline acetyltransferase.
• Acetylcholinesterase (AChE) is responsible for the hydrolysis of acetylcholine.
• The general SAR for muscarinic agonists includes:
  • A 5-atom rule between the quaternary nitrogen and the acyl group.
  • A nitrogen that can bear a positive charge.
  • An oxygen that can participate in hydrogen bonding.
  • A two-carbon spacer.
  • Introduction of a CH3 group on the α-carbon gives preferential nicotinic activity.

Acetylcholinesterase Inhibitors and Cholinergic Antagonists

• AChE hydrolyzes the ester group in acetylcholine.
• Reversible inhibitors of AChE include carbamates.
• Irreversible inhibitors of AChE include phosphate esters, which can undergo "ageing" and require an oxime to successfully hydrolyze.
• Muscarinic antagonists, such as atropine, have a general SAR that includes:
  • A ring system.
  • A quaternary nitrogen.
  • An ester group.

Serotonin

• Biosynthesis of serotonin involves tryptophan, tryptophan hydroxylase, and aromatic amino acid decarboxylase.
• Metabolism of serotonin involves MAO.
• The general SAR for arylpiperazines includes:
  • A piperazine ring.
  • A spacer.
  • A terminus.
• 5-HT1D receptors are involved in migraine.
• Triptans, such as zolmitriptan, are used to treat migraine.
• Serotonin reuptake inhibitors, such as SSRIs, block the removal of serotonin from the synapse.

Adrenergic Drugs

• Catecholamines, such as dopamine and norepinephrine, have a general structure and major metabolic pathways.
• The general SAR for phenylethanolamines includes:
  • A catechol group.
  • An amine group.
  • A hydroxyl group.
• Non-catecholamines are resistant to COMT metabolism.
• β-agonists, such as salbutamol, are used to treat asthma.
• β-antagonists, such as propranolol, are used to treat hypertension.
• α-antagonists, such as phentolamine, are used to treat hypertension.

Anxiolytics

• GABA receptors have three types of ligands: agonists, inverse agonists, and antagonists.
• Agonists, such as benzodiazepines, potentiate the action of GABA.
• Inverse agonists, such as β-carbolines, induce an action opposite to that of GABA.
• Antagonists, such as flumazenil, interact with the receptor but have no intrinsic activity.
• The general SAR for benzodiazepines includes:
  • A ring A with a Cl at C-7.
  • A ring B with a proton-accepting group at C-2.
  • A ring C with an aromatic group.

Hypnotics and Antiseizure Drugs

• Barbiturates, such as thiopental, are used as hypnotics.
• Ureides, such as phenytoin, are used as antiseizure drugs.
• The general SAR for barbiturates includes:
  • A short or long carbon chain or Ph ring at R and R'.
• The general SAR for ureides includes:
  • An imide functional group.

Antidepressants

• Major depressive disorders involve an imbalance of 5-HT and NE levels.
• TCA's, such as amitriptyline, are used to treat depression.
• The general SAR for TCA's includes:
  • A terminal amine group.
  • A 3-carbon spacer.
  • Halogen substitution at C-2.
• The general SAR for phenoxyphenylalkylamines includes:
  • Substitution at C-4 for SERT selectivity.
  • Substitution at C-2 for NET selectivity.
• Phenoxyphenylalkylamines, such as fluoxetine, are used to treat depression.### Dopamine and Antipsychotics
• The role of dopamine receptors in schizophrenia:
  • Probable link between increased dopamine levels and schizophrenia
  • Use of dopamine antagonists (at type 2 receptors) to treat schizophrenia
• General SAR for phenothiazines as antipsychotics:
  • Importance of the electron-withdrawing group
  • Nitrogen 3 carbons removed from the ring system
• General SAR for butyrophenone neuroleptics:
  • Key points: 4-carbon chain and the tertiary amine
• "New generation" antipsychotics represented by clozapine:
  • Supposed to have fewer extrapyramidal side effects

Dopamine and Parkinson's Disease

• Dopamine biosynthesis, metabolism, and dopaminergic neurotransmission:
  • Enzymes: tyrosine hydroxylase, aromatic amino acid decarboxylase
  • MAO and COMT
  • Type 1 and type 2 receptors
• Dopamine receptor agonists:
  • Levodopa and apomorphine
  • How levodopa works
• Mode of action of carbidopa:
  • Inhibitor of aromatic amino acid decarboxylase
  • Can't cross the blood-brain barrier (BBB)
• Dopamine metabolism inhibitors:
  • MAO and COMT inhibitors
  • Note structural similarity to natural substrate
  • Prolong the life of dopamine

Local and General Anaesthetics

• General SAR for the "ester type" local anaesthetics:
  • Procaine and benzocaine
  • Importance of the spacer and the type of R group
• General SAR for the "amide type" local anaesthetics:
  • Lidocaine
  • Importance of the type of R group and the spacer
• Inhaled anaesthetics:
  • Highly halogenated, low molecular weight compounds
• Metabolites and toxicity associated with fluorinated hydrocarbons:
  • Formation of radicals
  • Metabolism is not what you want

Opioid Analgesics

• Opioid receptor model:
  • Relation to the endorphins, morphine, and morphine analogues
• General SAR for morphine:
  • Modification at C-3, C-6, C-7, C-14, and tertiary amine
• Chemical modification of morphine by removal of ring systems:
  • No E-ring, no C and E rings, A-D ring analogues, and diphenylheptanones
  • Loss of rings gives compounds that are more flexible than morphine and sometimes more potent at mu receptors
• Importance of opioid metabolism:
  • N-dealkylation and conjugation
  • Metabolism products may retain activity or produce the active drug

Hints for EOT Exam

• Part A: 25 multiple-choice questions

• Part B: 7 short-answer questions

• Part C: One "long-answer" question

• EOT Exam is worth 40% of the course

• Some hints about answering questions:

  • Follow instructions
  • Do not repeat the question
  • Use a mechanistic rationale when necessary### Acids and Bases

• Acids have a pKa value, which is the negative logarithm of the acid dissociation constant.

• Conjugate bases are formed when an acid donates a proton.

• Examples of acids:

  • Phenol: pKa 9-11, conjugate base is phenolate.
  • Sulfonamide: pKa 9-10, conjugate base is sulfonamidate.
  • Imide: pKa 9-10, conjugate base is imidate.
  • Thiol: pKa 9-11, conjugate base is thiolate.
  • Carboxylic acid: pKa 4-6, conjugate base is carboxylate.
  • Sulfonic acid: pKa 0-1, conjugate base is sulfonate.

Bases

• Bases have a pKa value, which is the negative logarithm of the base association constant.
• Conjugate acids are formed when a base accepts a proton.
• Examples of bases:
  • Arylamine: pKa 4-5, conjugate acid is arylammonium.
  • Aromatic amine: pKa 5-6, conjugate acid is aromatic ammonium.
  • Imine: pKa 3-4, conjugate acid is iminium.
  • Alkylamine: pKa 9-11, conjugate acid is alkylammonium.
  • Guanidine: pKa 10-11, conjugate acid is guanidinium.

Neutral Functional Groups

• Examples of neutral functional groups:
  • Alkyl alcohol
  • Amide
  • Ketone and aldehyde
  • Ester
  • Ether
  • Nitrile
  • Sulfoxide
  • Quaternary ammonium

Reaction Mechanisms

• Rule number 1: Keep it simple.
• Nucleophiles and electrophiles are important in reaction mechanisms.
• Examples of nucleophiles and electrophiles:
  • Alcohols
  • Amines
  • Esters

General Introduction

• Topics covered in weeks 1-3:
  • Functional groups
  • Acids and bases
  • Lipophilicity
  • Ability of drugs to cross membranes
  • Inhibition of enzymes
  • Drug metabolism
• Phase 1 of drug metabolism: Introduction of new group
• Phase 2 of drug metabolism: Conjugation reaction to make water-soluble

Cardiovascular

• Topics covered in weeks 4, 5, and 6:
  • Diuretics
  • Ca2+ channel blockers
  • ACE inhibitors
  • Angiotensin II mimics
  • Cardiac glycosides
  • Cholesterol biosynthesis and cholesterol-lowering drugs (HMG-CoA reductase)

ANS

• Topics covered in weeks 8 and 9:
  • Acetylcholine - muscarinic and nicotinic receptors
  • AChE (irreversible inhibitors)
  • Adrenergic receptors (remember catechol amines and phenylethanolamines)
  • Serotonin - indole - 5-HT1 and 5-HT3

CNS

• Topics covered in weeks 10-12:
  • Anxiolytics (benzodiazepines)
  • Sedation (barbiturates)
  • Hypnotics (ureides)
  • Antidepressants
  • Dopamine - phenothiazines and Parkinson's disease
  • Local anaesthetics
  • Opioid analgesics (mu receptor)

Opioid Analgesics

• Opioid activity requires a specific structure
• Agonist activity is present when Me is attached to the nitrogen
• Antagonist activity is present when 3 to 5 carbons are attached to the nitrogen
• 14β OH increases analgesic activity, but significantly reduces antitussive activity
• Removal of the double bond enhances agonist activity
• Changing the functional group to OCH3 or ester reduces analgesic activity
• Changing the functional group to ketone or ester alters analgesic activity

Structures

• Important structures to remember:
  • Acetylcholine
  • Dopamine
  • γ-aminobutyric acid
  • Catechol
  • Norepinephrine
  • Serotonin
  • Benzodiazepines
  • Morphine