PHCHEM 205 LEC FINALS MEDICINAL ORGANIC CHEMISTRY

Flashcards from lecture notes on Medicinal Organic Chemistry, focusing on antimalarials and adrenergics.

mosquito that spreads Malaria

Anopheles Mosquito

mosquito that spreads Dengue, Chikungunya, and Zika?

Aedes Mosquito

meaning of the term 'mala aria'

Bad air

Cinchona Alkaloids

Quinine, Quinidine, Cinchonine, and Cinchonidine

toxic syndrome associated with Quinine and Quinidine

Cinchonism

symptoms of Cinchonism

Tinnitus, headache, nausea, and visual disturbances

major difference between 4-aminoquinolines and cinchona alkaloids

In 4-aminoquinolines, the 6’-methoxy is replaced w 7-chloro.

occurs when ferriprotoporphyrin IX combines with chloroquine

The drug lyses the parasite’s cell membrane, interfering w the parasite’s ability to digest hemoglobin or to synthesize nucleoproteins.

mefloquine mechanism of action (MOA)

Increases the parasite’s vesicular pH, interfering w its ability to process heme.

8-aminoquinolines quinoline substituents position

C-8

advantage of Primaquine

Destroys the exoerythrocytic forms before the parasite can infect erythrocytes.

fixed combination for prophylaxis and chloroquine-resistant P. falciparum

Sulfadoxine and Pyrimethamine

brand name for Sulfadoxine-Primethamine

Fansidar

Atovaquone and Proguanil HCl mechanism of action (MOA)

Atovaquone selectively inhibits the mitochondrial electron transport system, while proguanil is a prodrug metabolized to cycloguanil, which inhibits dihydrofolate reductase.

Doxycycline mechanism of action (MOA)

Prevents protein synthesis by reversibly inhibiting 30S ribosome subunits.

Quinacrine

most toxic antimalarial, is tumorgenic, mutagenic, and sclerosing.

key structural characteristic of Artemisinin

Trioxane (has endoperoxide and dioxepin oxygens).

Fosmidomycin

Selectively toxic: inhibits a biochem pathway not found in mammals, the nonmevalonate pathway to form isoprenoids.

What enzyme does fosmidomycin inhibit?

DOXP reductoisomerase enzyme

adrenergic receptors classification

α and β

produced when L-tyrosine is oxidized with tyrosine hydroxylase

Catechol amino acid, L-dopa.

generates norepinephrine (NE)

Dopamine β- hydroxylase

Gs G-protein coupled receptors

Increases AC and Ca currents

Gi G-protein coupled receptors

Decreases AC and increases K currents

Gq G-protein coupled receptors

Increases phospholipase A2 activity

enzyme found in neuronal mitochondria and inactivates some NE after uptake-1

MAO (monoamine oxidase)

effect of an OH at Rβ

Slows, but does not stop, CNS penetration

impact of catechol (R4 and R5 is OH)

Optimal direct action at all adrenoceptors, particularly β receptors; have low stability both in vivo (COMT metabolism) and in vitro (chemical and photo- oxidation); prohibits BBB penetration due to their hydrophilicity.

β2 selectivity if the N-substituent is i-propyl, t- butyl, or aralkyl

3,5-dihydroxyphenyl (resorcinol) ring

catechol drugs susceptible

Metabolism by COMT.

characteristics of long acting beta-selective drugs

Resorcinol or salicyl alcohol, and tert, iso, or aralkyl

functionality of Epinephrine

Potent vasoconstrictor (α) and cardiac stimulant (β)

dopamine is given IV since,

It is rapidly metabolized by COMT and MAO.

two types of actions for Adrenergic Agonists

Direct and Indirect

Indirect Adrenergic Agonists mechanism of action (MOA)

Augments NE’s action in receptors by stimulating its release from presynaptic terminals, blocking uptake-1, or inhibiting its metabolism

Phenylephrine uses

For severe hypotension from shock or drug admin., oral and topical nasal decongestant, dilates the pupil for open-angle glaucoma, used to prolong anesthesia in spinal anesthetics and prevent drops in BP.

required for α1- and α2- agonist activity of 2-arylimidazolines

Lipophilic substitution on the phenyl ring (ortho to the methylene bridge)

α2 Agonists therapeutic use

Antihypertensives, antiglaucoma drugs, and analgesics

clonidine brand name

Catapres

Clonidine mechanism of action (MOA)

Has peripheral α1 activity and specific binding to nonadrenergic imidazoline binding sites in the CNS, which inhibits sympathetic output.

tizanidine used for mechanism of action (MOA)

Centrally active muscle relaxant; reduces spasticity associated w cerebral or spinal cord injury.

Guanfacine and Guanabenz requirements

Phenyl ring requires at least one o-chlorine or o-methyl group.

active metabolite of Methyldopa

α-methylnorepinephrine

major indication that lead to the diminished use of Isoproterenol

Cardiac stimulation from β1 activity and lack of oral activity

net effect of Racemic (±) dobutamine?

β1

How does higher lipophilicity affect the duration of Beta-2 Agonists?

Results in membrane retention, delaying access to the β2-active site on the extracellular membrane surface.

Albuterol mechanism of action (MOA)

(S)-enantiomer: pro-inflammatory and enhances bronchial muscle contraction, bronchodilator efficacy is achieved at 1⁄4 dose of racemic albuterol, w marked reduction in side eYects.

long acting Beta-2 Agonists newest bronchodilator approved for use in chronic obstructive pulmonary disease (COPD)

Indacaterol (Arcapta® and Neohaler®)

molecule decreases the effectiveness of indirect-acting sympathomimetics

β-hydroxyl group

Wh molecule increases the effectiveness of indirect-acting sympathomimetics

α-methyl group

What is L-(+)-Pseudoephedrine used for?

OTC nasal decongestants and cold medications.

What makes ephedrine have good oral activity?

Does not have phenolic substituents giving it a mixed-acting response, resistant to MAO and COMT.

What is the advantages and disadvantages of Nonselective Alpha Blockers?

Alpha 1 blockade causes vasodilation, and alpha 2 blockade causes reflex tachycardia.

What type of reaction does Phenoxybenzamine undergo?

Alkylates α-receptors, causes long lasting (3-4 days) and irreversible α blockade, as it changes the shape of the receptor, nitrogen mustards (highly reactive alkylating agents).

What is Phentolamine used for?

Used to treat episodes of pheochromocytoma.

What does the alpha-1 receptor blockade, in Quinazoline Αlpha 1 Blockers do?

Produce peripheral vasodilation w/out increasing heart rate or cardiac output.

First-dose phenomenon

Dose-dependent eYect characterized by postural hypotension and syncope; minimized by giving an initial low dose.

What is required for α1 receptor activity on a

Quinazoline ring: 4-amino group

Tamsulosin

Treats BPH w little effect on blood pressure

What does Yohimbine do?

Increases heart rate and bp as a result of blocking α2 receptors in the CNS.

Why does Mirtazapine increase the amount of NE and serotonin?

Tetracyclic α2 blocker

How was Propranolol first made?

Inserting an oxymethylene bridge into the arylethanolamine of pronethalol yields propranolol, the first clinically successful aryloxypropanolamine β-blocker

Selective β1 antagonism

Achieved w p-monosubstituted phenyl rings

What are the uses of Propranolol

Hypertension, arrhythmia, angina pectoris, hypertrophic cardiomyopathy, pheochromocytoma, and migraine prophylaxis

Nadolol

Longest acting beta blocker; undergoes very little hepatic metabolism, hence its half- life is about 20-24 hours.

Sotalol

Blocks the inward K+ current that delays cardiac repolarization; antiarrhythmic

Pindolol

Modest membrane-stabilizing activity and significant intrinsic β- agonistic activity

Specific advantages of selective beta 1 blockers

Safe for patients w bronchitis or bronchial asthma, and absence of β2 blockade, which mediates vasodilation

Unique characteristics of Hydrophilic beta blockers

Metabolized by kidneys (SANE: setolol, atenolol nadolol, esmolol) are given at lower doses for those w kidney diseases.

Short DOA (about 20 to 30 minutes) from its ester

Esmolol (Brevibloc)

Nebivolol

Unique β1-blockers as it has a nitric oxide (NO) potentiating eYect.

Mixed Alpha and Beta Blockers

Antihypertensives w α1, β1 and β2 blocking activity

What is different about selective activity between Labetalol and Carvedilol?

α receptor-blocking action produces vasodilation, and β-receptor blocking eYects prevents reflex tachycardia. VS Only the S enantiomer has β-blocking activity, estimated to be 10- to 100- fold of its α-blocking activity.

Metyrosine

Competitively inhibits tyrosine hydroxylase; limited clinical use: helps control hypertensive episodes and other symptoms of catecholamine overproduction in patients w pheochromocytoma.