Med Chem - Calcium Channel Blockers, ACE I's, ARBS, Renin Inhib, a1/a2 antagonists/agonists Flashcards
4 chemical classes of calcium channel blockers
give an example of a drug from each
1,4-dihydro pyridines (nifedipine)
phenylalkyl amines (verapamil)
benzothiazepines (diltiazem)
diaminopropanol ethers (bepridil)
the MAJORITY of calcium channel blockers are from which chemical class
1,4-dihydro pyridines
all of the 4 chemical classes of calcium channel blockers are _______. BUT which class is less so and why?
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
how is the lipophilicity of 1,4-DHP’s enhanced?
by larger esters on R2 and R3 and by disubstituted phenyl rings
true or false
all calcium channel blockers are lipophilic with good oral bioavailability
true
all calcium channel blockers except ___ contain at least 1 chiral carbon
nifedipine
they are used as racemic mixtures – effect not known
which enantiomer of verapamil is more potent
S
true or false
the calcium channel blockers do not undergo extensive first pass metabolism
FALSE - they do
2 main enzymes in the Renin-Angiotensin Pathway
renin
ACE (angiotensin converting enzyme)
purpose of the enzymes in the Renin-Angiotensin pathway (renin and ACE)
to release angiotensin II from angiotensinogen
effects of angiotensin 2
potent vasoconstrictor - affects peripheral resistance, renal function, CV structure
ACE degrades _______
what does this do
degrades BRADYKININ
bradykinin is a natural vasodilatory that stimulates prostaglandin synthesis and natiuresis (release of sodium in urine)
explain how inhibiting ACE would help to lower blood pressure
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
briefly explain the sequence of events in the renin-angiotensin pathway
angiotensinogen -> angiotensin I through RENIN
angiotensin I -> angiotensin II thru ACE
substrate of ACE
angiotensin I
which 2 amino acids on the active site of ACE ionically bind to angiotensin 1
lysine or arginine
which amino acid on ACE composes the hydrophobic pocket of the enzyme
leucine
aside from LYS/ARG/LEU
what other interaction is important in angiotensin binding to ACE
zinc bonding
ACE inhibitors must have:
-affinity for ____
-a ___ group to bind ____
-capable of binding to ____
-stable to ____
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!)
***captopril binds to the active site of ACE and does what?
PREVENTS THE CONVERSION OF ANGIOTENSIN i TO II
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?
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
explain what Log P means
relate to enalapril
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
is enalapril highly protein bound?
50-60% – pretty high bv high acidity
how is enalapril eliminated
kidney
true or false
enalapril does not have the side effects of rash and loss of taste seen with captopril
TRUE
bc it doesn’t have thiol group like captopril does
food and enalapril
food does NOT affect absorption
true or false
esters exist in ACE inhibitors to be a binding site for zinc
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)
which is more highly protein bound and why- enalapril or fosinopril
fosinopril bc it has phosphinate instead of carboxylate
phosphinate is more acidic
angiotensin 2 is an octapeptide produced how?
by the conversion of angiotensin I through ACE
4 ways in which angiotensin II produces vasoconstriction
-direct vasoconstriction
-increased catecholamine release
-causes release of aldosterone
-hypertrophy of vascular and cardiac cells
name and explain the ARB receptor subtypes
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!
original research to block the AT1 receptor (beginnings of ARBS) were done with what?
peptide analogs, specifically saralasin
however, peptide analogs ended up being partial agonists and lack oral bioavailability
saralasin mimics….
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)
define peptidomimetics
molecules that mimic peptide action but have NO PEPTIDE BONDS and MW is less then 700daltons
true or false
losartan is a prodrug
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
how does the oxidation of losartan by CYP2C9 and CYP3A4 make it more active?
because the OH is oxidized to carboxylic acid
carboxylic acid exhibits much better hydrogen bonding than OH
name the only renin inhibitor
Aliskiren
advantage of aliskiren over ACE inhibitors and ARBS
aliskiren does not cause a compensatory increase in renin
aliskiren is a renin inhibitor developed as….
a NON-PEPTIDE mimic of the octapeptide that renin recognizes in angiotensinogen (the substrate)
MOA aliskiren
by inhibiting renin, aliskiren directly inhibits the formation of angiotensin I and angiotensin 2
how many chiral centers of aliskiren contain
4
aliskiren should not be used (contraindicated) with ACE inhibitors or ARBS in which patients? why?
diabetic patients bc of the risk of renal impairment, hypotension, hyperkalemia
ARBS and ACE inhibitors should not be used in which patients
with mod-severe renal impairment (less than 60 mL/min)
true or false
alskiren is poorly absorbed
true
only 2.5% bioavailable and 90% excreted unchanged in the feces
name and explain the 2 main types of alpha adrenergic receptors
a1 receptor and a2 receptor
a1 receptor is associated with the contraction of vascular smooth muscle
a2 receptor associated with inhibition of norepinephrine release
explain what a nonselective alpha antagonist would be expected to do
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
3 chemical classes of alpha antagonists
name which are nonselective/selective
- B-haloalkylamines - nonselective
- Imidazoline antagonists - nonselective
- quinazoline derivatives - alpha 1 selective!
name a B-haloalkylamine that is a nonselective alpha antagonist
phenoxybenzamine
explain the MOA of phenoxybenzamine
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
2 clinical uses for phenoxybenzamine
pheochromocytoma
treat peripheral vascular resistance (Raynaud’s)
2 reasons the aziridinium ion formed from phenoxybenzamine is so electrophilic
-3 membered ring structure has a lot of strain
-N has a (+) charge which is not favored
2 drugs in the imidazoline alpha antagonist class
are they nonselective or selective?
tolazoline, phentolamine
nonselective
chemically, selective a1 antagonists are….
quinazoline derivatives containing a substituted piperazine ring
2 key pieces that are ESSENTIAL for alpha 1 (selective) antagonists
which piece is not essential?
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
explain how central a2 agonists work
they stimulate a2 receptors in the CNS
this results in a reduction in sympathetic outflow to the CV system, resulting in a hypotensive effect.
adverse effects of central a2 agonists
sedation, bradycardia, mental depression
bc they reduce sympathetic outflow
**how are alpha 2 agonists able to have CNS effects such as sedation and mental depression??
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
explain the metabolism of clonidine
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
name 2 central a2 adrenergic agonists
clonidine and methyldopa
methyldopa
a2 agonist
its a prodrug
phenylethylamine derivative
explain the metabolism of methyldopa
how does it get through the BBB and into the brain?
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
