Med Chem - Calcium Channel Blockers, ACE I's, ARBS, Renin Inhib, a1/a2 antagonists/agonists

Question 1

4 chemical classes of calcium channel blockers

give an example of a drug from each

Answer 1

1,4-dihydro pyridines (nifedipine)

phenylalkyl amines (verapamil)

benzothiazepines (diltiazem)

diaminopropanol ethers (bepridil)

Question 2

the MAJORITY of calcium channel blockers are from which chemical class

Answer 2

1,4-dihydro pyridines

Question 3

all of the 4 chemical classes of calcium channel blockers are _______. BUT which class is less so and why?

Answer 3

all 4 classes are basic

1,4 DHP’s are less basic (except amlodipine and nicardipine)

this is bc at physiologic pH, 1,4-DHP’s are unionized, and the other classes are ionized.

unionized bc the Nitrogen in 1,4-DHP’s is conjugated to the esters

Question 4

how is the lipophilicity of 1,4-DHP’s enhanced?

Answer 4

by larger esters on R2 and R3 and by disubstituted phenyl rings

Question 5

true or false

all calcium channel blockers are lipophilic with good oral bioavailability

Answer 5

true

Question 6

all calcium channel blockers except ___ contain at least 1 chiral carbon

Answer 6

nifedipine

they are used as racemic mixtures – effect not known

Question 7

which enantiomer of verapamil is more potent

Answer 7

S

Question 8

true or false

the calcium channel blockers do not undergo extensive first pass metabolism

Answer 8

FALSE - they do

Question 9

2 main enzymes in the Renin-Angiotensin Pathway

Answer 9

renin
ACE (angiotensin converting enzyme)

Question 10

purpose of the enzymes in the Renin-Angiotensin pathway (renin and ACE)

Answer 10

to release angiotensin II from angiotensinogen

Question 11

effects of angiotensin 2

Answer 11

potent vasoconstrictor - affects peripheral resistance, renal function, CV structure

Question 12

ACE degrades _______

what does this do

Answer 12

degrades BRADYKININ

bradykinin is a natural vasodilatory that stimulates prostaglandin synthesis and natiuresis (release of sodium in urine)

Question 13

explain how inhibiting ACE would help to lower blood pressure

Answer 13

ACE degrades bradykinin. bradykinin is a vasodilator and promotes the release of sodium in the urine, helping to lower BP

thus, inhibiting ACE would prevent the degradation of bradykinin and bradykinin would be able to produce its positive effects on blood pressure

Question 14

briefly explain the sequence of events in the renin-angiotensin pathway

Answer 14

angiotensinogen -> angiotensin I through RENIN

angiotensin I -> angiotensin II thru ACE

Question 15

substrate of ACE

Answer 15

angiotensin I

Question 16

which 2 amino acids on the active site of ACE ionically bind to angiotensin 1

Answer 16

lysine or arginine

Question 17

which amino acid on ACE composes the hydrophobic pocket of the enzyme

Answer 17

leucine

Question 18

aside from LYS/ARG/LEU
what other interaction is important in angiotensin binding to ACE

Answer 18

zinc bonding

Question 19

ACE inhibitors must have:

-affinity for ____
-a ___ group to bind ____
-capable of binding to ____
-stable to ____

Answer 19

affinity for the ACE active site

anionic group to bind the cationic Arg residue on ACE

capable of binding to zinc

stable to the hydrolytic attack of the Glutamate carboxylate anion (otherwise would be converted to product!)

Question 20

***captopril binds to the active site of ACE and does what?

Answer 20

PREVENTS THE CONVERSION OF ANGIOTENSIN i TO II

Question 21

Give 3 examples of what can serve as the zinc binding group in ACE inhibitors

do any show the BEST zinc binding? despite this, is it used a lot?

Answer 21

sulfhydryl/thiol (-SH)

carboxylate COOH-CH-NH

phosphanate OH-P=O

sulfhydryl shows the best zinc binding. however, not really used a lot bc skin rashes and loss of taste. can form disulfides which shortens duration of action. — lot (-) things to body. - really only seen in captopril

Question 22

explain what Log P means

relate to enalapril

Answer 22

log P of enalapril is 0.71 - pretty low. can’t cross the membrane that well

high logP = more hydrophobic. around 2-3.5 is ideal

Question 23

is enalapril highly protein bound?

Answer 23

50-60% – pretty high bv high acidity

Question 24

how is enalapril eliminated

Answer 24

kidney

Question 25

true or false

enalapril does not have the side effects of rash and loss of taste seen with captopril

Answer 25

TRUE

bc it doesn’t have thiol group like captopril does

Question 26

food and enalapril

Answer 26

food does NOT affect absorption

Question 27

true or false

esters exist in ACE inhibitors to be a binding site for zinc

Answer 27

FALSE

esters themselves do not bind zinc

they are hydrolyzed to expose the underlying zinc binding group, which THEN binds zinc directly (thiol, carboxylate, phosphinate)

Question 28

which is more highly protein bound and why- enalapril or fosinopril

Answer 28

fosinopril bc it has phosphinate instead of carboxylate

phosphinate is more acidic

Question 29

angiotensin 2 is an octapeptide produced how?

Answer 29

by the conversion of angiotensin I through ACE

Question 30

4 ways in which angiotensin II produces vasoconstriction

Answer 30

-direct vasoconstriction
-increased catecholamine release
-causes release of aldosterone
-hypertrophy of vascular and cardiac cells

Question 31

name and explain the ARB receptor subtypes

Answer 31

AT1 and AT2

AT1 subtype is the one responsible for CV effects of angiotensin II. (AT2 effects are unkown)
therefore, AT1 is logical target for antihypertensives!

Question 32

original research to block the AT1 receptor (beginnings of ARBS) were done with what?

Answer 32

peptide analogs, specifically saralasin

however, peptide analogs ended up being partial agonists and lack oral bioavailability

Question 33

saralasin mimics….

Answer 33

angiotensin 2

saralasin MOA is to block the AT1 receptor and bind in place of angiotensin 2

(however this drug is a peptidomimetic and was not successful)

Question 34

define peptidomimetics

Answer 34

molecules that mimic peptide action but have NO PEPTIDE BONDS and MW is less then 700daltons

Question 35

true or false

losartan is a prodrug

Answer 35

FALSE

losartan IS 14% oxidized by CYP2C9 and 3A4 to an active metabolite, however the original drug still did have activity, the metabolism just made it more active than before

Question 36

how does the oxidation of losartan by CYP2C9 and CYP3A4 make it more active?

Answer 36

because the OH is oxidized to carboxylic acid

carboxylic acid exhibits much better hydrogen bonding than OH

Question 37

name the only renin inhibitor

Answer 37

Aliskiren

Question 38

advantage of aliskiren over ACE inhibitors and ARBS

Answer 38

aliskiren does not cause a compensatory increase in renin

Question 39

aliskiren is a renin inhibitor developed as….

Answer 39

a NON-PEPTIDE mimic of the octapeptide that renin recognizes in angiotensinogen (the substrate)

Question 40

MOA aliskiren

Answer 40

by inhibiting renin, aliskiren directly inhibits the formation of angiotensin I and angiotensin 2

Question 41

how many chiral centers of aliskiren contain

Answer 41

4

Question 42

aliskiren should not be used (contraindicated) with ACE inhibitors or ARBS in which patients? why?

Answer 42

diabetic patients bc of the risk of renal impairment, hypotension, hyperkalemia

Question 43

ARBS and ACE inhibitors should not be used in which patients

Answer 43

with mod-severe renal impairment (less than 60 mL/min)

Question 44

true or false

alskiren is poorly absorbed

Answer 44

true

only 2.5% bioavailable and 90% excreted unchanged in the feces

Question 45

name and explain the 2 main types of alpha adrenergic receptors

Answer 45

a1 receptor and a2 receptor

a1 receptor is associated with the contraction of vascular smooth muscle

a2 receptor associated with inhibition of norepinephrine release

Question 46

explain what a nonselective alpha antagonist would be expected to do

Answer 46

lower blood pressure by inhibiting a1 vasoconstriction, BUT also block the INHIBITION of norepinephrine release (by blocking a2), therefore this would lead to fast heart rate and increased cardiac output

therefore, to lower blood pressure, we would need an alpha 1 antagonist or an alpha 2 agonist

want to make as selective as possible

Question 47

3 chemical classes of alpha antagonists

name which are nonselective/selective

Answer 47

1. B-haloalkylamines - nonselective
2. Imidazoline antagonists - nonselective
3. quinazoline derivatives - alpha 1 selective!

Question 48

name a B-haloalkylamine that is a nonselective alpha antagonist

Answer 48

phenoxybenzamine

Question 49

explain the MOA of phenoxybenzamine

Answer 49

IRREVERSIBLE covalent inhibition of the alpha receptors

this occurs bc the Cl on phenoxybenzamine is a very good leaving group, and an aziridinium ion will form

this aziridinium ion is highly electrophilic and highly reactive

thus, a nucloephile on the alpha receptor will attack a carbon in the aziridinium ion, resulting in an ALKYLATED RECEPTOR — its now covalently linked to phenoxybenzamine

Question 50

2 clinical uses for phenoxybenzamine

Answer 50

pheochromocytoma

treat peripheral vascular resistance (Raynaud’s)

Question 51

2 reasons the aziridinium ion formed from phenoxybenzamine is so electrophilic

Answer 51

-3 membered ring structure has a lot of strain

-N has a (+) charge which is not favored

Question 52

2 drugs in the imidazoline alpha antagonist class
are they nonselective or selective?

Answer 52

tolazoline, phentolamine

nonselective

Question 53

chemically, selective a1 antagonists are….

Answer 53

quinazoline derivatives containing a substituted piperazine ring

Question 54

2 key pieces that are ESSENTIAL for alpha 1 (selective) antagonists

which piece is not essential?

Answer 54

quinazoline ring and piperidine/piperizine ring system is ESSENTIAL

the R substituent on the piperidine/piperizine ring is not essential for action and just affects the pharmacokinetics

Question 55

explain how central a2 agonists work

Answer 55

they stimulate a2 receptors in the CNS

this results in a reduction in sympathetic outflow to the CV system, resulting in a hypotensive effect.

Question 56

adverse effects of central a2 agonists

Answer 56

sedation, bradycardia, mental depression

bc they reduce sympathetic outflow

Question 57

**how are alpha 2 agonists able to have CNS effects such as sedation and mental depression??

Answer 57

because the imidazoline ring nitrogens are LESS BASIC due to the conjugation with the benzene ring
(phenyliminoimidazoline derivatives)

this results in an UNIONIZED form that can cross the BBB

Question 58

explain the metabolism of clonidine

Answer 58

clonidine is an a2 agonist that works by binding and activating a2 receptors in the BRAIN

therefore, it is a hydrophobic molecule in order to cross the BBB. however, being very hydrophobic, it’s also metabolized extensively

it is first OXIDIZED by CYP450. into p-HYDROXY clonidine. this metabolite is INACTIVE bc the OH makes the molecule too polar to cross the BBB - cannot have hypotensive effect

glucuronidation takes care of the rest

Question 59

name 2 central a2 adrenergic agonists

Answer 59

clonidine and methyldopa

Question 60

methyldopa

Answer 60

a2 agonist

its a prodrug

phenylethylamine derivative

Question 61

explain the metabolism of methyldopa

how does it get through the BBB and into the brain?

Answer 61

methyldopa is a PRODRUG

metabolized twice (decarboxylase, then hydroxylase) to form the active form - ALPHA-METHYLNOREPINEPHRINE which is a SELECTIVE A2 COMPOUND

methyldopa is actively transported in the brain. in the brain, it is metabolized to its active form to exert hypotensive action