Med Chem Part 2 Flashcards
explain in detail the mechanism in which arachidonic acid is converted into PGG2
there is endoperoxide formation between carbon 11 and carbon 9 of arachidonic acid. a 5 membered cyclopentane ring is also formed, through a free radical reaction (single electron transfer)
within the COX enzyme, there is a free radical attached to Tyr385. this free radial picks up a proton from carbon 13 of the molecule and becomes OH-cyclohexane-tyrosine-385
because of this, the double bond switches from carbon 14 to carbon 13, and there is now a free radical at carbon 15.
this free radical combines with peroxide radical (OOH)
THIS FORMS PG2
explain in detail the mechanism of PGG2 conversion to PGH2
the peroxide is reduced to hydroxyl and becomes PGH2
through PEROXIDASE enzyme
the O free radical on Tyr-385 is REGENERATED and the prostaglandin synthesis cycle is continued
what is paracetamol
another name for tylenol (acetaminophen)
what inhibits the POX step of the biosynthesis of prostaglandins? where? what is the result?
paracetamol/acetaimophen
in the brain
the Tyr385 free radical will not be regenerated. the PG synthesis cycle will not be continued
what step allows the prostaglandin synthesis cycle to be regenerated and continued?
the reduction of the peroxide on PGG2 to OH forms the free radical with tyrosine 358
this allows the cycle to continue. this radical takes a proton from the altered arachidonic acid molecule (that just formed endoperoxide between carbons 11 and 9), causing the double bond to switch from 14 to 13, and a free radical is generated on carbon 15, which which combines with free radical peroxide to produce PGG2….. etc
explain the structural features that a drug (NSAID) must have to block COX enzyme
the drug, like arachidonic acid, must be a LIPOPHILIC ACID. the entire molecule must be lipophilic acid from a carboxylic acid group
true or false
NSAIDS compete with arachidonic acid for the active site of COX, and therefore they must be similar in structure
true
why is it that an NSAID must have a carboxylic acid?
(aside from the fact that arachidonic acid has this feature)
because within the active site of COX, there is an Arginine amino acid with a guanidinium side chain. the NH3 has a POSITIVE CHARGE, and therefore, a COO- will be highly attracted to it
explain the 2 interactions that must occur for a potential drug molecule to bind to the active sites of COX
- Arginine amino acid within COX has a positive charge and must have an IONIC INTERACTION with COO- on the drug molecule. both NH3+ and COO- are ionized at physiologic pH
- the hydrogen on carbon 13 of the molecule must be abstracted by the free radical of Tyrosine 385 within COX
name 2 main fates of PGH2
forms TXA2 and PGI2
through which enzyme is PGH2 converted to TxA2?
thromboxane synthetase
through what enzyme is PGH2 converted into PGI2?
what is another name for PGI2?
prostacyclin synthetase
another name for PG12 is prostacyclin
in which location is PGH2 mainly converted to PGI2 or prostacyclin?
what enzyme mediates this?
endothelial cells of blood vessels
COX2 MEDIATED
name the actions of TxA2 and PGI2 (prostacyclin)
where do they mainly exist?
TxA2 is a potent vasoCONSTRICTOR and induces platelet aggregation (clotting)
PGI2 or prostacyclin has opposite functions
it is a potent vasoDILATOR and INHIBITS clotting/platelet aggregation
are TXA2 and PGI2 mediators of inflammation?
NO involved in clotting (or not) and vasoconstriction (TxA2) and dilation (PGI2)
where do TxA2 and PGI2 come from?
PGH2
where is TxA2 primarily located?
what enzyme mediates?
in PLATELETS
it is COX1 mediated
true or false
the biosynthesis of PGI2 is COX1 mediated
FALSE - COX2
true or false
PGI2 is a potent vasodilator
true
ALL prostaglandins have what relative half life?
EXTREMELY short - 1-5 mins
for which is there more of a concern — COX1 selective inhibitors or COX2?
why?
COX2 selective inhibitors because they essentially block the formation PGI2
PGI2 “balances out” the clotting and vasodilation associated with TxA2.
thrombosis is thus a concern
what is the only NSAID on the market that is COX2 selective
celecoxib
as mentioned, all prostaglandins have a extremely short half life of 1-5mins
name 2 mechanisms in which prostaglandins are inactivated and thus have a very short half life
name the 2 enzymes involved
- the oxidation of C15-OH to C15-keto (PG-15-OH dehydrogenase)
- The reduction of C13=C14 (by delta13 reductase enzyme)
explain why non selective inhibition of both COX1 and COX2 is preferred for NSAIDS
because through doing this, the balance between formation of TxA2 and PGI2 is maintained because TxA2 is COX1 mediated and PGI2 is COX2 mediated
why is aspirin LOW DOSE preferred for the prophylaxis of heart attack and stroke?
because it is NONSELECTIVE
true or false
tylenol has NO inflammatory action
true - only antipyretic and analgesic
explain the nomenclature of the 2 chains of prostaglandins and what this means about their chemistry
the COOH bearing chain is always alpha
the -OH bearing open chain is beta
thus, they are projected in opposite (TRANS directions)
true or false
in prostaglandins, the chain that contains COOH is always beta
FALSE - always alpa
in prostaglandin naming, what do the capital letters represent?
the nature and stereochemistry of the O substituent on carbons 9 and 11 of the cyclopentane ring***
in naming prostaglandins, what does the subscript number represent?
the number of carbon double bonds OUTSIDE of the cyclopentane ring (2)
if a prostaglandin is named with an an alpha symbol, what does this mean?
what about beta?
what about alpha, beta?
alpha - C9, C11 both have alpha substituents
beta - C9 and C11 both have beta substituents
a,b - C9-alpha, C11-beta
_____________ in naming of prostaglandins indicates the nature and stereochemistry of the O substituent on C9 and C22
capital letters
true or false
acetaminophen is a COX inhibitor
TRUE
true or false
Acetaminophen is a selective COX1 inhibitor
FALSE
nonselective
name 2 salicylic acid derivative NSAIDS
aspirin
diflunisal
indole and indene acetic acid COX inhibitors AND aryl/heteroaryl acetaic acids can also be called what?
phenacs
name 3 NSAIDS that are Indole and Indene acetic acid phenacs
Sulindac
indomethacin
etodalac
name 3 NSAIDS that are aryl/heteroaryl acetic acid phenacs
Tolmetin
Diclofenac
Ketorolac
what is the structural name for profens?
arylpropionic acids
name 5 profens (arylpropionic acids)
ibuprofen
naproxen
flurbiprofen
ketoprofen
fenoprofen
profens are also called….
arylpropionic acids
what are fenemates?
name 2
anthranilic acids
mefenamic acid
meclofenamic acid
what is another name for enolic acids
oxicams
name 2 enolic acids (oxicams)
piroxicam
meloxicam
name an alkanone that is a nonselective NSAID
nabumetone
what is the warning that comes with celecoxib and why?
if patient has prior history of cardiac disease they must be closely monitored
this is bc COX2 selective inhibitors throw off the balance between PGI2 and TxA2
TxA2 is overpowering. this promotes clotting and vasoconstriction and can lead to thrombosis
structure of celecoxib
di-aryl substituted pyrazole
