[MEDICINAL CHEMISTRY] Parasympathetic System & CNS Depressants

a. Parasympathetic system

Also known as Cholinergic system

a. Parasympathetic system

b. Sympathetic system

c. Acetylcholine (ACh)

Neurotransmitter of the parasympathetic system.

a. Norepinephrine

b. Dopamine

c. Acetylcholine (ACh)

d. Epinephrine

b. Muscarinic (M) and Nicotinic (N)

Receptors of the parasympathetic system are:

a. Alpha and Beta
b. Muscarinic (M) and Nicotinic (N)
c. D1 and D2
d. 5-HT1 and 5-HT2

c. Acetylcholinesterase (AChE)

Acetylcholine is metabolized by which enzyme?

a. Monoamine oxidase (MAO)

b. Catechol-O-methyltransferase (COMT)

c. Acetylcholinesterase (AChE)

d. Tyrosine hydroxylase

b. Serine decarboxylase

The enzyme that converts:

• L-serine → Ethanolamine.

a. Choline-N-methyl transferase
b. Serine decarboxylase
c. Choline-acetyl transferase (ChAT)
d. Acetylcholinesterase

c. Choline-N-methyl transferase

The enzyme that converts:

• Ethanolamine → Choline.

a. Serine decarboxylase
b. Choline-acetyl transferase (ChAT)
c. Choline-N-methyl transferase
d. Acetylcholinesterase

c. Choline-acetyl transferase (ChAT)

The enzyme that converts:

• Choline → Acetylcholine.

a. Serine decarboxylase
b. Choline-N-methyl transferase
c. Choline-acetyl transferase (ChAT)
d. Acetylcholinesterase

b. Acetylcholinesterase (AChE)

The enzyme that converts:

• Acetylcholine (ACh) → Choline + Acetic Acid.

a. Choline-acetyl transferase (ChAT)

b. Acetylcholinesterase (AChE)

c. Choline-N-methyl transferase

d. Serine decarboxylase

c. Acetylcholine (ACh)

Prototype cholinergic agonist.

a. Bethanechol

b. Carbachol

c. Acetylcholine (ACh)

d. Methacholine

c. Acetylcholine (ACh)

Prototype cholinergic agonist that is prone to hydrolysis and non-selective.

a. Bethanechol

b. Carbachol

c. Acetylcholine (ACh)

d. Pilocarpine

b. Hydrolysis

Acetylcholine (ACh) is a prototype cholinergic that is prone to _______

a. Oxidation
b. Hydrolysis
c. Reduction
d. Alkylation

b. Prone to hydrolysis and non-selective

Problems of Acetylcholine (ACh) as a cholinergic agonist include being:

a. Prone to oxidation and selective
b. Prone to hydrolysis and non-selective
c. Prone to reduction and hepatotoxic
d. Prone to alkylation and nephrotoxic

b. Non-selective

Acetylcholine (ACh) is _____

a. Selective

b. Non-selective

a. Stability to stomach HCl and esterases

Requirements for an ideal cholinergic agonist include _____

a. Stability to stomach HCl and esterases
b. Instability to stomach HCl and esterases
c. Lipophilicity and high protein binding
d. Poor absorption and rapid excretion

a. Addition of Carbamate

• Less prone to susceptibility

a. Addition of Carbamate

b. Addition of Alkyl group

c. Carbachol

Addition of carbamate to ACh produces which drug?

a. Methacholine
b. Bethanechol
c. Carbachol
d. Pilocarpine

c. Carbachol

More stable ester, resulting to long-acting effect

a. Methacholine

b. Bethanechol

c. Carbachol

d. Pilocarpine

c. Carbachol

Used for glaucoma

a. Methacholine

b. Bethanechol

c. Carbachol

d. Pilocarpine

b. Addition of Alkyl group

• Less prone to susceptibility and more selective to muscarinic than nicotinic

a. Addition of Carbamate

b. Addition of Alkyl group

c. Methacholine

Addition of an alkyl group to ACh produces which drug?

a. Carbachol

b. Bethanechol

c. Methacholine

d. Acetylcholine

c. Methacholine

More stable on muscarinic over nicotinic receptors

a. Carbachol

b. Bethanechol

c. Methacholine

d. Acetylcholine

c. Methacholine

Used for the diagnosis of asthma

a. Carbachol

b. Bethanechol

c. Methacholine

d. Acetylcholine

b. Bethanechol

Carbachol (carbamate) + Metacholine (alkyl) = ________

a. Carbachol

b. Bethanechol

c. Methacholine

d. Acetylcholine

b. Bethanechol

More selective on muscarinic over nicotinic receptors

a. Carbachol

b. Bethanechol

c. Methacholine

d. Acetylcholine

b. Bethanechol

Used to stimulate GIT and urinary bladder after surgery

a. Carbachol

b. Bethanechol

c. Methacholine

d. Acetylcholine

d. Tyrosine hydroxylase

The enzyme that converts:

Tyrosine → L-DOPA

a. Aromatic L-amino acid decarboxylase
b. Dopamine β-hydroxylase
c. Phenyl ethanolamine N-methyl transferase (PENMT)
d. Tyrosine hydroxylase

b. Aromatic L-amino acid decarboxylase

The enzyme that converts:

L-DOPA → Dopamine

a. Tyrosine hydroxylase
b. Aromatic L-amino acid decarboxylase
c. Dopamine β-hydroxylase
d. Phenyl ethanolamine N-methyl transferase (PENMT)

c. Dopamine β-hydroxylase

The enzyme that converts:

Dopamine → Norepinephrine

a. Tyrosine hydroxylase
b. Aromatic L-amino acid decarboxylase
c. Dopamine β-hydroxylase
d. Phenyl ethanolamine N-methyl transferase (PENMT)

d. Phenyl ethanolamine N-methyl transferase (PENMT)

The enzyme that converts:

Norepinephrine → Epinephrine

a. Tyrosine hydroxylase
b. Aromatic L-amino acid decarboxylase
c. Dopamine β-hydroxylase
d. Phenyl ethanolamine N-methyl transferase (PENMT)

a. Norepinephrine (NE)

DOC for septic shock

a. Norepinephrine (NE)

b. Epinephrine

c. Dobutamine

b. Epinephrine

DOC for anaphylactic shock

a. Norepinephrine (NE)

b. Epinephrine

c. Dobutamine

c. Dobutamine

DOC for cardiogenic shock

a. Norepinephrine (NE)

b. Epinephrine

c. Dobutamine

b. Vanillylmandelic Acid (VMA)

Norepinephrine and Epinephrine are metabolized by MAO and COMT to:

a. Homovanillic Acid (HVA)

b. Vanillylmandelic Acid (VMA)

c. 5-Hydroxyindoleacetic Acid (5-HIAA)

d. Phenylacetic acid

c. Homovanillic Acid (HVA)

Dopamine is metabolized by MAO and COMT to:

a. Vanillylmandelic Acid (VMA)

b. 5-Hydroxyindoleacetic Acid (5-HIAA)

c. Homovanillic Acid (HVA)

d. Phenylacetic acid

a. MAO and COMT

_______ are enzymes involved in the metabolism of catecholamines such as norepinephrine, epinephrine, and dopamine.

a. MAO and COMT
b. AChE and ChAT
c. Tyrosine hydroxylase and DOPA decarboxylase
d. PENMT and Dopamine β-hydroxylase

b. Epinephrine, norepinephrine, and dopamine

📌Mnemonics: “END”

MAO and COMT are enzymes involved in the metabolism of catecholamines such as:

a. Serotonin, histamine, and GABA
b. Epinephrine, norepinephrine, and dopamine
c. Acetylcholine, glutamate, and aspartate
d. Melatonin, oxytocin, and vasopressin

a. β-phenylethylamine

[Structure Activity Relationship of β-phenyl ethylamine]

Parent structure of sympathomimetic amines.

a. β-phenylethylamine
b. Tyramine
c. Phenylethanolamine
d. Catechol

b. 2 carbon atoms

[Structure Activity Relationship of β-phenyl ethylamine]

The distance between the aromatic ring and the amino group in sympathomimetic amines should be:

a. 1 carbon atom

b. 2 carbon atoms

c. 3 carbon atoms

d. 4 carbon atoms

b. 1R Configuration

[Structure Activity Relationship of β-phenyl ethylamine]
Which optical isomer configuration of sympathomimetic amines is more potent?

a. 1S Configuration

b. 1R Configuration

c. 2R Configuration

d. 2S Configuration

• Increased β-agonist activity

• Reduced α-agonist activity

[Structure Activity Relationship of β-phenyl ethylamine]

Substitution on the nitrogen (N) of sympathomimetic amines with increase in size and bulkiness results in:

a. Decreased β-agonist activity, increased α-agonist activity

b. Increased β-agonist activity, reduced α-agonist activity

c. Increased α-agonist activity only

d. Decreased both α and β activity

a. Substitution on the nitrogen (N)

[Structure Activity Relationship of β-phenyl ethylamine]
Substitution on the _________ of sympathomimetic amines with increase in size and bulkiness results in:

• Increased β-agonist activity

• Reduced α-agonist activity

a. Substitution on the nitrogen (N)

b. Substitution on the alpha carbon

b. Substitution on the alpha carbon

[Structure Activity Relationship of β-phenyl ethylamine]
Substitution on the _______ of sympathomimetic amines tends to:

• Blocks oxidation by MAO and increases duration of action

• Increased oral absorption and CNS activity

• Addition of a methyl group provides α2 selectivity

a. Substitution on the nitrogen (N)

b. Substitution on the alpha carbon

d. All of the above

• Blocks oxidation by MAO and increases duration of action

• Increased oral absorption and CNS activity

• Addition of a methyl group provides α2 selectivity

[Structure Activity Relationship of β-phenyl ethylamine]

Substitution on the alpha carbon of sympathomimetic amines tends to _____

a. Blocks oxidation by MAO and increases duration of action

b. Increased oral absorption and CNS activity

c. Addition of a methyl group provides α2 selectivity

d. All of the above

c. Methyldopa

[Structure Activity Relationship of β-phenyl ethylamine]
Example of an alpha-methylated sympathomimetic amine with α2 selectivity.

a. Dopamine
b. Epinephrine
c. Methyldopa
d. Isoproterenol

b. 3' and 4' OH

[Structure Activity Relationship of β-phenyl ethylamine]
Presence of _______ groups on the aromatic ring of sympathomimetic amines provides maximal α and β activity and direct acting activity.

a. 2' and 5' OH
b. 3' and 4' OH
c. 4' and 5' OH
d. 2' and 4' OH

a. Maximal α and β activity, direct acting activity

[Structure Activity Relationship of β-phenyl ethylamine]
Presence of 3' and 4' OH groups on the aromatic ring of sympathomimetic amines provides _______

a. Maximal α and β activity, direct acting activity

b. Indirect acting activity only

c. Resistance to COMT

d. Decreased oral absorption

3' and 4' OH

[Structure Activity Relationship of β-phenyl ethylamine]
Without _______ on the aromatic ring, sympathomimetic amines are resistant to COMT (increased DOA) and provide Indirect acting activity

a. 2' and 5' OH

b. 3' and 4' OH

c. 4' and 5' OH

d. 2' and 4' OH

b. Resistant to COMT (increased DOA) and indirect acting

[Structure Activity Relationship of β-phenyl ethylamine]
Without 3' and 4' OH groups on the aromatic ring, sympathomimetic amines are ______ and provide _______ activity.

a. Resistant to MAO and direct acting
b. Resistant to COMT (increased DOA) and indirect acting
c. Susceptible to COMT and direct acting
d. Resistant to AChE and mixed acting

b. 3' OH

[Structure Activity Relationship of β-phenyl ethylamine]

Which hydroxyl group on the aromatic ring is important for alpha (α) activity?

a. 4' OH

b. 3' OH

c. 2' OH

d. 5' OH

d. 4' OH

[Structure Activity Relationship of β-phenyl ethylamine]

Which hydroxyl group on the aromatic ring is important for beta (β) activity?

a. 3' OH

b. 5' OH

c. 2' OH

d. 4' OH

b. Benzodiazepines

Most widely used anxiolytic.

a. Barbiturates

b. Benzodiazepines

c. Buspirone

d. Zolpidem

c. Benzodiazepines

MOA: Increases the frequency of GABA-mediated chloride ion channel opening.

a. Barbiturates

b. Buspirone

c. Benzodiazepines

d. Zaleplon

a. Ring A

[Structure Activity Relationship of Benzodiazepine]

The electron-attractive substituents on_______ of benzodiazepines enforce activity.

a. Ring A

b. Ring B

c. Ring C

d. Fused triazole ring

b. Ring B

[Structure Activity Relationship of Benzodiazepine]

Which ring of benzodiazepines is necessary for activity?

a. Ring A

b. Ring B

c. Ring C

d. Fused ring

c. Ring C (specifically “C-5”)

[Structure Activity Relationship of Benzodiazepine]

The electron-attractive substituents with small volume on the benzene ring of ______ will enforce activity.

a. Ring A

b. Ring B

c. Ring C

d. All rings

b. Increased activity and binding

[Structure Activity Relationship of Benzodiazepine]

If an electron-withdrawing group (EWG) such as halogen or nitro is substituted at position 7 on Ring A of benzodiazepines, what is the effect?

a. Decreased activity and binding

b. Increased activity and binding

c. No effect

d. Complete loss of activity

b. NO₂ > Br > CF₃ > Cl

[Structure Activity Relationship of Benzodiazepine]

Rank the following electron-withdrawing groups at position 7 on Ring A of benzodiazepines from most to least active.

a. Cl > Br > NO₂ > CF₃

b. NO₂ > Br > CF₃ > Cl

c. Br > CF₃ > Cl > NO₂

d. CF₃ > NO₂ > Br > Cl

b. Decreased activity

[Structure Activity Relationship of Benzodiazepine]

Substitution on positions 6, 8, and 9 of Ring A in benzodiazepines results in:

a. Increased activity

b. Decreased activity

c. Increased half-life

d. No change in activity

b. Weaker activity and affinity

[Structure Activity Relationship of Benzodiazepine]

If Ring A of benzodiazepines is a heterocyclic ring instead of an aromatic ring, what is the effect on activity and affinity?

a. Increased activity and affinity

b. Weaker activity and affinity

c. No change

d. Complete loss of activity

c. Histidine

[Structure Activity Relationship of Benzodiazepine]

The proton-accepting group (carbonyl oxygen) at position 2 on Ring B of benzodiazepines is necessary to interact with which receptor amino acid?

a. Serine

b. Cysteine

c. Histidine

d. Tyrosine

b. Faster excretion

[Structure Activity Relationship of Benzodiazepine]

Addition of a hydroxyl (OH) group at position 3 on Ring B of benzodiazepines results in:

a. Longer duration of action

b. Faster excretion

c. Increased potency

d. Increased lipophilicity

b. Decreased activity

[Structure Activity Relationship of Benzodiazepine]

Addition of an alkyl substituent at position 3 on Ring B of benzodiazepines results in:

a. Increased activity

b. Decreased activity

c. Prolonged half-life

d. No effect

b. 5-phenyl Ring C

[Structure Activity Relationship of Benzodiazepine]

The ______ Ring C of benzodiazepines is not required for binding but contributes favorable steric or hydrophobic interactions.

a. 3-hydroxy
b. 5-phenyl
c. 7-nitro
d. 2-carbonyl

b. Decreased activity

[Structure Activity Relationship of Benzodiazepine]

Substitution at the para position on Ring C of benzodiazepines results in:

a. Increased activity
b. Decreased activity
c. Increased selectivity
d. No effect

b. Not detrimental to agonist activity

[Structure Activity Relationship of Benzodiazepine]

Substitution at the meta position on Ring C of benzodiazepines is:

a. Detrimental to agonist activity
b. Not detrimental to agonist activity
c. Essential for agonist activity
d. Causes complete loss of activity

b. Pharmacologically active benzodiazepine derivatives with high affinity to the receptor

[Structure Activity Relationship of Benzodiazepine]

Annelating the 1,2-bond of Ring B with an additional electron-rich ring such as triazole or imidazole results in:

a. Loss of pharmacological activity

b. Pharmacologically active benzodiazepine derivatives with high affinity to the receptor

c. Increased toxicity only

d. Decreased oral absorption

b. Triazolobenzodiazepines

Benzodiazepine fused with a triazolo ring

a. Imidazobenzodiazepines
b. Triazolobenzodiazepines
c. Nitrobenzodiazepines
d. Hydroxybenzodiazepines

a. Short-acting

Triazolobenzodiazepine is _____

a. Short-acting

b. Long-acting

• Triazolam

• Alprazolam

Triazolobenzodiazepine examples.

a. Triazolam and Alprazolam
b. Midazolam and Flurazepam
c. Diazepam and Chlordiazepoxide
d. Lorazepam and Oxazepam

b. Imidazobenzodiazepines

Benzodiazepine fused with an imidazole ring

a. Triazolobenzodiazepines
b. Imidazobenzodiazepines
c. Nitrobenzodiazepines
d. Chlorobenzodiazepines

a. Short-acting

Imidazobenzodiazepines is ______

a. Short-acting

b. Long-acting

c. Midazolam

Imidazobenzodiazepine example is _____

a. Triazolam

b. Alprazolam

c. Midazolam

b. Barbiturates

Was used extensively as CNS depressants.

a. Benzodiazepines

b. Barbiturates

c. Buspirone

d. Zolpidem

b. Barbiturates

MOA: Increases the duration of GABA-mediated chloride ion channel opening.

a. Benzodiazepines

b. Barbiturates

c. Buspirone

d. Zaleplon

a. 2,4,6-trioxohexahydropyrimidine (Barbituric acid)

Nucleus of barbiturates is:

a. 2,4,6-trioxohexahydropyrimidine (Barbituric acid)
b. 1,4-benzodiazepine
c. β-phenylethylamine
d. Pyrimidine

a. Barbituric acid

2,4,6-trioxohexahydropyrimidine.

a. Barbituric acid
b. Thiopental
c. Phenobarbital
d. Secobarbital

b. Activity

[Structure Activity Relationship of Barbiturate]

At position 5 of barbiturates, addition of alkyl or aryl groups confers:

a. Toxicity
b. Activity
c. Water solubility
d. Shorter duration

b. Thiobarbiturates

At position 2 of barbiturates, if sulfur (S) replaces oxygen (O), the resulting drugs are called:

a. Oxobarbiturates

b. Thiobarbiturates

c. Aminobarbiturates

d. Halobarbiturates

• Rapid CNS penetration

• Short duration

• More lipid soluble

Thiobarbiturates are characterized by:

a. Slow CNS penetration, long duration, less lipid soluble

b. Rapid CNS penetration, short duration, more lipid soluble

c. Poor oral absorption, long duration, water soluble

d. No CNS activity, long duration, protein bound

c. Thiopental

Example of a thiobarbiturate.

a. Phenobarbital

b. Pentobarbital

c. Thiopental

d. Secobarbital