Chemical Pharmacology I: Acetylcholine Agonists
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Questions and Answers

What structural change should be made to the group attached to Nitrogen (R1) to make it bigger?

NHtBu

What change should be made to R2 by adding a CH3?

Add a CH3 to the carbon that bears the NH2 group

Which structural features allow aryloxypropanolamines like atenolol to act at adrenergic receptors?

Superimposing the aromatic rings leads to Nitrogen and hydroxyl functionalities occupying similar positions in space

What is the significance of adding a hydroxyl at C-3 for benzodiazepines?

<p>Adding a hydroxyl at C-3 results in compounds with comparable activity but faster excretion</p> Signup and view all the answers

What is the most important structural feature responsible for the activity of ureides?

<p>Imide functional group</p> Signup and view all the answers

What is the key difference between butyrophenone and pimozide in terms of antipsychotic activity?

<p>Pimozide has a longer duration of action</p> Signup and view all the answers

Discuss the structural relationship between the phenothiazine and dopamine.

<p>The structural relationship between phenothiazine and dopamine should be elaborated on.</p> Signup and view all the answers

What are some topics covered in the General introduction section of Chemical Pharmacology I?

<p>functional groups, acids &amp; bases, lipophilicity, ability of drugs to cross membranes, Inhibition of enzymes (reversible versus irreversible), Drug metabolism (phase 1 and phase 2)</p> Signup and view all the answers

Which of the following are classes of drugs covered under Cardiovascular in Chemical Pharmacology I? (Select all that apply)

<p>ACE inhibitors</p> Signup and view all the answers

AChE inhibitors are reversible.

<p>False</p> Signup and view all the answers

___________ are irreversible inhibitors of AChE.

<p>Organophosphates</p> Signup and view all the answers

Match the following neurotransmitters with their structures:

<p>Acetylcholine = HO-C-CH3-N(CH3)3 Dopamine = HO-C-C6H3(OH)2-CH2-CH2-NH2 Serotonin = HO-C-CH2-CH(NH2)-CO2H</p> Signup and view all the answers

What is the primary purpose of the 'End of Trimester Exam'?

<p>To assess the knowledge acquired throughout the trimester.</p> Signup and view all the answers

In the 'End of Trimester Exam', what is the weightage of Part A that consists of multiple-choice questions?

<p>25 marks</p> Signup and view all the answers

How many Short Answer Questions are there in Part B of the 'End of Trimester Exam'?

<p>7</p> Signup and view all the answers

What is the weightage of the 'Long-Answer' Question in the 'End of Trimester Exam'?

<p>20 marks</p> Signup and view all the answers

Which part of the 'End of Trimester Exam' allows students to choose between two questions?

<p>Part C</p> Signup and view all the answers

What do students need to use during the 'End of Trimester Exam'?

<p>Calculator</p> Signup and view all the answers

If students require assistance during the 'End of Trimester Exam', how can they reach out?

<p>Call (5552 7021), email (<a href="mailto:[email protected]">[email protected]</a>), or visit level 4, G25, and knock firmly on the door.</p> Signup and view all the answers

What is the significance of the co-administration of carbidopa with levodopa in the treatment of Parkinson's disease?

<p>Carbidopa inhibits the decarboxylase enzyme, increasing the amount of levodopa reaching the brain.</p> Signup and view all the answers

How does carbidopa elicit its activity in the treatment of Parkinson's disease?

<p>Carbidopa inhibits the decarboxylase enzyme.</p> Signup and view all the answers

What is the purpose of carbidopa in Parkinson's disease therapy?

<p>Carbidopa acts to increase the amount of levodopa that reaches the brain.</p> Signup and view all the answers

How does carbidopa affect levodopa metabolism in the treatment of Parkinson's disease?

<p>Carbidopa inhibits the conversion of levodopa to dopamine.</p> Signup and view all the answers

What enzyme does carbidopa inhibit in the treatment of Parkinson's disease?

<p>Decarboxylase enzyme</p> Signup and view all the answers

What is responsible for the hydrolysis of acetylcholine?

<p>Acetylcholinesterase (AChE)</p> Signup and view all the answers

What does acetylcholinesterase (AChE) hydrolyze in acetylcholine?

<p>The ester group</p> Signup and view all the answers

Why are phosphate esters stable to hydrolysis?

<p>Because they are NOT electron deficient</p> Signup and view all the answers

What functional group is required to successfully hydrolyze phosphate esters?

<p>Oxime</p> Signup and view all the answers

What is the '5-atom rule' in acetylcholine agonists?

<p>For maximum agonist activity, a hydrogen must be 5 atoms removed from the N+</p> Signup and view all the answers

What is the most important group to introduce on the alpha-carbon for preferential nicotinic activity in acetylcholine?

<p>Methyl group (Me)</p> Signup and view all the answers

What enzyme is involved in metabolizing serotonin?

<p>Monoamine oxidase (MAO)</p> Signup and view all the answers

What enzyme is involved in breaking down catecholamines?

<p>Catechol-O-methyl transferase (COMT)</p> Signup and view all the answers

What is the structural change needed in norepinephrine to improve selectivity at b-receptors?

<p>Add an oxymethylene bridge</p> Signup and view all the answers

What single structural change in norepinephrine would make it resistant to MAO metabolism?

<p>Replace the 3,4-diol group with a 3-CH2OH &amp; a 4-OH group</p> Signup and view all the answers

Study Notes

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

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Description

Review of Week 8 Lecture on Acetylcholine Agonists, covering muscarinic and nicotinic cholinergic receptors, biosynthesis of acetylcholine, and importance of acetylcholinesterase.

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