Med Chem Part 2 Flashcards by amanda kastel

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

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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

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what is paracetamol

another name for tylenol (acetaminophen)

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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

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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

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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

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true or false

NSAIDS compete with arachidonic acid for the active site of COX, and therefore they must be similar in structure

true

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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

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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

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name 2 main fates of PGH2

forms TXA2 and PGI2

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through which enzyme is PGH2 converted to TxA2?

thromboxane synthetase

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through what enzyme is PGH2 converted into PGI2?
what is another name for PGI2?

prostacyclin synthetase

another name for PG12 is prostacyclin

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in which location is PGH2 mainly converted to PGI2 or prostacyclin?
what enzyme mediates this?

endothelial cells of blood vessels

COX2 MEDIATED

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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

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are TXA2 and PGI2 mediators of inflammation?

NO involved in clotting (or not) and vasoconstriction (TxA2) and dilation (PGI2)

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where do TxA2 and PGI2 come from?

PGH2

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where is TxA2 primarily located?
what enzyme mediates?

in PLATELETS

it is COX1 mediated

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true or false

the biosynthesis of PGI2 is COX1 mediated

FALSE - COX2

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true or false

PGI2 is a potent vasodilator

true

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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