MED CHEM EXAM 1

Norepinephrine Synthesis

Norepinephrine Synthesis

Tyrosine → (Hydroxylation) → L-Dopa → (Decarboxylation) → Dopamine → (Hydroxylation) → Norepinephrine

Ortho vs Meta vs Para

ROMP

Activation of α2 receptor inhibits the ________

enzyme adenylate cyclase.

Inactivation of adenylate cyclase → decreases cAMP → → inhibition of further release of norepinephrine (uses negative feedback).

Epinephrine (EPI) has a poor oral bioavailability due to extensive metabolism by ______

MAO and COMT

Norepinephrine 

Epinephrine

Epinephrine MOA

Think of sympathetic signaling!

Activates a1 → Vasoconstriction → Good for hypotension

Activates a1 → Vasoconstriction → Good for nasal decongestant (dilation)

Why should catecholamines like NE and Epinephrine be stored away from light?

Bases and lights cause it to oxidize, leading to an ortho-quinone, which then can react with your DNA=bad.

That is why they are always formulated with antioxidants.

Why would you use Epinephrine?

Causes vasoconstriction (leading to hypertension in the sympathetic response) and also dilating blood vessels in mucus membranes (dilate to increase airflow). You want it’s vasodilatory effect.

Thus it also used for allergic rhinitis when the airways close up why? To cause bronchodilation!

What is the problem with ortho-quinone?

Toxic and it can react with DNA, protein, GSH and others.

Epinephrine and all other catechols are chemically susceptible to _______

oxygen and other oxidizing agents, especially in the presence of base and/or light, quickly decomposing to inactive quinones.

All catechol-containing drugs are stabilized with ______

antioxidants and dispensed in air-tight amber containers.

Epinephrine, also known as adrenaline, is used to treat a number of conditions, including ___________

anaphylaxis, cardiac arrest, asthma, and superficial bleeding

Anaphylaxis

A severe, potentially life-threatening allergic reaction.

The reaction can occur within seconds or minutes of exposure to an allergen.

Symptoms include a skin rash, nausea, vomiting, difficulty breathing, and shock.

If not treated right away, usually with epinephrine, it can result in unconsciousness or deat

Epinephrine infusions may also be used for symptomatic _____

bradycardia.

Since it causes your HR to go up, and bradycardia is when your HR is too SLOW.

Bradycardia is a type of arrhythmia, or abnormal heart rhythm, that occurs when the heart beats slower than ______

60 beats per minute (bpm).

Epinephrine (Epi Pen) usually is administered slowly by intravenous (IV) injection to relieve a__________  not controlled by other treatments

acute asthmatic attacks

Phenylethanolamine

Common structure for 1 of 2 classes of a1 agonists

Alpha 1 agonists are spilt into what two classes?

2-arylimidazoline

Phenylethanolamine

2-arylimidazoline

Common structure for 1 of 2 classes of a1 agonists

a1 agonist MOA

Stimulates phospholipase C activity.

What is it used for? Vasoconstriction, mydriasis; used for the treatment of hypotension, nasal decongestants, and during eye exams.

-azoline

Alpha 1 agonists that are apart of the 2-arylimidazoline class 

Phenylethanolamine Alpha 1 Agonists

2-arylimidazoline Alpha 1 agonists 

Suffix: “azoline”

Phenylephrine Structure

Class: Alpha 1 agonists with the phenylethanolamine backbone.

Phenylephrine 

Very frequently found in over-the-counter (OTC) decongestants in cold medications

Short duration of action of less than 4 hrs 

Class: Alpha 1 agonists with the phenylethanolamine backbone.

Structure:

Metaraminol

Alpha 1 agonist used for the treatment of hypotension

Class: Alpha 1 agonists with the phenylethanolamine backbone. 

Midodrine

Alpha 1 agonist for orthostatic hypotension

Do=A prodrug that does require conversion to the active metabolite, desglymidodrine

Midodrine Structure

Key: Midodrine does require metabolism to its active metabolite, desglymidodrine

Class: Alpha 1 agonists with the phenylethanolamine backbone. 

Midodrine Metabolism

Class: Alpha 1 agonists with the phenylethanolamine backbone. 

Alpha 1 Agonists Class w/ phenylehtanolamine backbone

Methoxamine

Midodrine 

Metaminol 

Phenylephrine 

Amidephrine 

NE (Why? The structure is essentially NE minus the two OHs on the catechol!)

Imadazole vs Imidazoline pKAs

Alpha 1 2-aryl imidazoline agonists need a lip_____

ophillic substitution at the ortho position of the phenyl ring

Structure-activity relationship of arylimidazoline agonists

Lipophilic ortho position is required. 

Lipophilic meta/para substitution helps to provide selectivity for the alpha 1 receptor. 

Mixed-acting agonists

Ephedrine

Pseudoephedrine

MOA: Bind to both alpha and beta adrenoreceptors and displace NE from synaptic vesicles or inhibit their uptake, thus increasing NE concentration at the adrenergic receptors.

Used in cold medications with antihistamines.

Ephedrine 

Not a substrate for COMT nor MAO. Why? The alpha methyl group sterically hinders its metabolism.

Class: Mixed acting sympathomimetic (targets alpha, beta receptors, and also increases NE concentration).

What is ephedrine regulated?

Ephedrine → Methamphetamine (Meth) 

Loratadine Structure

Antihistamine

Diphenhydramine Structure 

Antihistamine

Pseudoephedrine Use

Nasal decongestant (in combo OTC products e.g., Claritin-D)

Structure:

Used in products like Zyrtec-D (Allergy + Sinus) and Advil Cold and Sinus. 

Arylimidazoline adrenergic agonists are highly ionic in nature.

They are widely used in topical preparations as nasal decongestants and eye drops for conditions associated with the common cold, influenza, sinusitis, allergic and nonallergic rhinitis, and upper respiratory track infections

Ephedrine is not a substrate for ___ and ___

COMT; MAO

Not for MAO because of the presence of an alpha-methyl group which sterically hinders metabolism by MAO.

Fexofenadine Structure

Certizine Structure

Mixed-acting sympathomimetics are common ingredients in many ______ with oral decongestant formulations

cold medications

Mixed-acting sympathomimetics:

Ephedrine

Pseudoephedrine

Ibuprofen Structure 

α2 agonist Uses 

Antihypertensive, treatment of glaucoma, sedative & treatment of opiate dependence and alcohol withdrawal symptoms. 

**Even though it’s in the brain! Activates the receptor to lead to a decrease in NE which decreases BP. 

Alpha 2 agonists Structures

Suffix “idine”, all contain the aminoadamine backbone.

Alpha 2 agonists Nomenclature Exceptions 

Monoxide → HT 

Guanfacine → HT 

Guanabenz →  HT

Methyldopa →  HT

Mnemonic: Asma and Aliza (a2) watched “Good Morning Ginny”.

Clonidine

Used for hypertension

Tablets, Injection, Transdermal System

Due to it’s CNS Side Effects it cannot treat gluacoma

Clonidine

Class: Alpha 2 agonist with a 2-aminoimidazoline backbone.

Used for Hypertension

So it’s an alpha 2 agonist, think about how Clonidine affects the brain, so the “inidine” suffixes all pertain to that drug class.

Apraclonidine vs Clonidine

Apraclonidine contains an NH2 polar group, which will cause it to be highly ionized at a physiological pH, so it’s less likely to cross the BBB.

Clonidine=cutesy and demure; it will cross the blood-brain barrier → HT

Brimonidine does a little bit of both → crosses the BBB for fatigue and glaucoma use

Suffix: -nidine

Alpha 2 agonists 

Apraclonidine

Brimonidine

Alpha 2 agonists used to treat glaucoma

-nidine: Alpha 2 agonists 

Apraclonidine vs Brimonidine

Apraclonidine: Poor BBB penetration → fewer CNS effects

Brimonidine: Crosses BBB → may cause fatigue/drowsiness

Why? Apraclonidine is highly ionized at a normal pH (can’t cross) and Brimonidine is very lipophillic

2-Arylimidazoline VS 2-aminoimidazoline

Outlier: Lofexidine which is an alpha 2 agonist but doesn’t have the 2-aminoimadzoline backbone

2-Arylimidazoline vs 2-aminoimidazoline Clinical Use

2-Arylimidazoline: Alpha 1 agonist for nasal decongestant (the other class for alpha 1 was for hypotension also).

2-aminoimidazoline: Alpha 2 agonist for hypertension, glaucoma

Methyldopa

Also like midodrine both are prodrugs that need to be converted to their activie metabolite 

But methyldopa is alpha 2, hypertension and midodrine is alpha 1 for hypotension

Guanfacine, guanabenz, and moxonide are used for the treatment of _____

hypertension

All alpha 2 agonists!

What does the 2-arylimidazoline vs 2-aminoimidazoline rings require for activity? 

2-arylimidazoline: Liophilic ortho substitution and needs an Imidazoline Ring 

2-aminoimidazoline: Phenyl needs one ortho Chlorine or Methy,l but the Imidazoline Ring not required 

Tizanidine

“idine” → Alpha 2 agonist

Used for muscle spasticity due to spinal cord injury or multiple sclerosis

Tizanidine readily crosses the ________ reducing spasticity by increasing presynaptic inhibition of motor neurons

BBB where it functions as a α2 -adrenergic agonist

“idine” → Alpha 2 agonist

Tizanidine

Alpha 2 agonist that readily crosses the BBB and is used for the treatment of muscle spasticity.

All alpha 2 agonist have the 2-aminoimidazoline backbone except….

Also…Guanfacine, Guanabenz, Moxonidine, Methyldopa

Lofexidine is an agonist of α2 adrenergic receptor and used for the treatment of _____ symptoms in adults (approved in 2018)

opioid withdrawal

“idine” → Alpha 2 agonist

Does not have a 2-aminoimidazoline backbone!

Guanfacine Structure

Used for Hypertension

Class: Alpha 2 agonist, but does not contain the 2-aminoimidazole backbone like lofexidine.

**Open ring analog of clonidine.

Systolic vs Diastolic Pressure

Systolic → Blood pumped out of the heart

Diastolic → Resting state between heartbeats

Guanabenz Structure

Used for Hypertension

Class: Alpha 2 agonist, but does not contain the 2-aminoimidazole backbone like lofexidine.

**Open ring analog of clonidine. 

Moxonidine Structure 

Used for Hypertension

Class: Alpha 2 agonist, but does not contain the 2-aminoimidazole backbone like lofexidine

What do the structures of Guanfacine, guanabenz, and moxonide reveal for alpha 2 agonists?

The imidazoline ring was not necessary for the activity, but the phenyl ring requires at least one ortho chlorine or methyl group

Methyldopa

Used for the treatment of hypertension

An alpha 2 agonist that does require conversion to its active metabolite to be selective for the alpha 2 agonist.

Dexmedetomidine is an agonist of α2 adrenergic receptor which was approved for the ____

sedation purpose (approved in 2020)

“idine” → Alpha 2 agonist

Also decreases blood pressure and heart rate!!  

What do the structures of Guanfacine, guanabenz indicate for alpha 2 agonist?

The imidazoline ring was not necessary for the activity, but the phenyl ring requires at least one ortho chlorine or methyl group.

Is methyldopa the active form of the drug?

No, it’s the active metabolite that is so.

What part of molecules does COMT metabolize?

The catecholamine

For Sudafed, by not having a catecholamine means that it will not be metabolized by COMT but since it has a methyl it will be by MAO.

Apraclonidine vs Clonidine 

Apraclonidine: Contains an NH2 group which is polar 

This means that it will not cross the BBB like clonidine making it a better candidate for glaucoma (in the eye) than clonidine. 

“pril”

ACE inhibitors 

“sartan”

ARBs

Normal HT 

Less than 120 (Systolic) 

Less than 80 (Diastolic) 

Anything higher than these values is HT 

140/90 mmHG

High Blood Pressure

What is the first line of therapies for patients with high blood pressure?

Thiazide Diuretics

Calcium Channel Blockers

Angiotensin-Converting Enzymes

** Beta-blockers if this treatment options fail

ABCD

First line therapies for hypertension

A: Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors) 

B: Beta Blockers 

C: Calcium Channel Blockers 

D: Diuretics 

ARBs suffix

“sartan”

Calcium Channel Blockers suffix

“dipine”

Diuretics Suffix

“ide”

Beta Agonists Classes

____ β-blockers are often preferred in patients with respiratory conditions like asthma or COPD due to their reduced effect on bronchoconstriction compared to non-selective β-blockers.

Selective

Dobutamine

β1 adrenergic agonist used as a cardiac stimulant after surgery or congestive heart failure (IV only)

Dobutamine Structure

Only B1 agonist.

Catechol Structure allows it to be quickly degraded by COMT, which is used as a cardiac stimulant after congestive heart failure. 

How does the structure of dobutamine effect it’s metabolism?

Contains a catechol: Metabolized by COMT 

Thus, it has a short duration of action and no oral activity. 

Dobutamine is an example of what?

Beta 1 agonist 

All SABAs are resistant to COMT metabolism except what?

Isoetharine 

What is the common structure in short-acting Beta agonists (SABAs)?

Resorcinol

This prevents COMT metabolism and allows SABA to be slowly metabolized by MAO.

This indicates that the structure is what?

SABA (Resorcinol)

Structures of SABAs

It contains a Resorcinol that is not metabolized by COMT but by MAO.

But also, the MAO metabolism is slow because the nitrogens are very sterically hindered, making it harder for them to be metabolized.

Exception: Isoetharine

Metaproterenol vs Terbutaline

Short-acting β2 agonists → Used for COPD/Asthma

Terbutaline: Can be used for long-term treatment since the nitroge

is more sterically hindered, increasing the time it takes for MAO metabolism to occur.

How can albuterol be administered?

Inhaled or orally

What makes levalbuterol so special?

This is the R enantiomer of albuterol.

Meaning that compared to the structure of epinephrine, this will be bind to the B2 receptors more potently because it structure is similar to that of epinephrine (natural sympathetic analog which triggers bronchodilation).