Podcast
Questions and Answers
What structural change should be made to the group attached to Nitrogen (R1) to make it bigger?
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?
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?
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?
What is the significance of adding a hydroxyl at C-3 for benzodiazepines?
Signup and view all the answers
What is the most important structural feature responsible for the activity of ureides?
What is the most important structural feature responsible for the activity of ureides?
Signup and view all the answers
What is the key difference between butyrophenone and pimozide in terms of antipsychotic activity?
What is the key difference between butyrophenone and pimozide in terms of antipsychotic activity?
Signup and view all the answers
Discuss the structural relationship between the phenothiazine and dopamine.
Discuss the structural relationship between the phenothiazine and dopamine.
Signup and view all the answers
What are some topics covered in the General introduction section of Chemical Pharmacology I?
What are some topics covered in the General introduction section of Chemical Pharmacology I?
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)
Which of the following are classes of drugs covered under Cardiovascular in Chemical Pharmacology I? (Select all that apply)
Signup and view all the answers
AChE inhibitors are reversible.
AChE inhibitors are reversible.
Signup and view all the answers
___________ are irreversible inhibitors of AChE.
___________ are irreversible inhibitors of AChE.
Signup and view all the answers
Match the following neurotransmitters with their structures:
Match the following neurotransmitters with their structures:
Signup and view all the answers
What is the primary purpose of the 'End of Trimester Exam'?
What is the primary purpose of the 'End of Trimester Exam'?
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?
In the 'End of Trimester Exam', what is the weightage of Part A that consists of multiple-choice questions?
Signup and view all the answers
How many Short Answer Questions are there in Part B of the 'End of Trimester Exam'?
How many Short Answer Questions are there in Part B of the 'End of Trimester Exam'?
Signup and view all the answers
What is the weightage of the 'Long-Answer' Question in the 'End of Trimester Exam'?
What is the weightage of the 'Long-Answer' Question in the 'End of Trimester Exam'?
Signup and view all the answers
Which part of the 'End of Trimester Exam' allows students to choose between two questions?
Which part of the 'End of Trimester Exam' allows students to choose between two questions?
Signup and view all the answers
What do students need to use during the 'End of Trimester Exam'?
What do students need to use during the 'End of Trimester Exam'?
Signup and view all the answers
If students require assistance during the 'End of Trimester Exam', how can they reach out?
If students require assistance during the 'End of Trimester Exam', how can they reach out?
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?
What is the significance of the co-administration of carbidopa with levodopa in the treatment of Parkinson's disease?
Signup and view all the answers
How does carbidopa elicit its activity in the treatment of Parkinson's disease?
How does carbidopa elicit its activity in the treatment of Parkinson's disease?
Signup and view all the answers
What is the purpose of carbidopa in Parkinson's disease therapy?
What is the purpose of carbidopa in Parkinson's disease therapy?
Signup and view all the answers
How does carbidopa affect levodopa metabolism in the treatment of Parkinson's disease?
How does carbidopa affect levodopa metabolism in the treatment of Parkinson's disease?
Signup and view all the answers
What enzyme does carbidopa inhibit in the treatment of Parkinson's disease?
What enzyme does carbidopa inhibit in the treatment of Parkinson's disease?
Signup and view all the answers
What is responsible for the hydrolysis of acetylcholine?
What is responsible for the hydrolysis of acetylcholine?
Signup and view all the answers
What does acetylcholinesterase (AChE) hydrolyze in acetylcholine?
What does acetylcholinesterase (AChE) hydrolyze in acetylcholine?
Signup and view all the answers
Why are phosphate esters stable to hydrolysis?
Why are phosphate esters stable to hydrolysis?
Signup and view all the answers
What functional group is required to successfully hydrolyze phosphate esters?
What functional group is required to successfully hydrolyze phosphate esters?
Signup and view all the answers
What is the '5-atom rule' in acetylcholine agonists?
What is the '5-atom rule' in acetylcholine agonists?
Signup and view all the answers
What is the most important group to introduce on the alpha-carbon for preferential nicotinic activity in acetylcholine?
What is the most important group to introduce on the alpha-carbon for preferential nicotinic activity in acetylcholine?
Signup and view all the answers
What enzyme is involved in metabolizing serotonin?
What enzyme is involved in metabolizing serotonin?
Signup and view all the answers
What enzyme is involved in breaking down catecholamines?
What enzyme is involved in breaking down catecholamines?
Signup and view all the answers
What is the structural change needed in norepinephrine to improve selectivity at b-receptors?
What is the structural change needed in norepinephrine to improve selectivity at b-receptors?
Signup and view all the answers
What single structural change in norepinephrine would make it resistant to MAO metabolism?
What single structural change in norepinephrine would make it resistant to MAO metabolism?
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
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Description
Review of Week 8 Lecture on Acetylcholine Agonists, covering muscarinic and nicotinic cholinergic receptors, biosynthesis of acetylcholine, and importance of acetylcholinesterase.
