Nitrocatechols act as Catechol-O-methyl transferase (COMT) inhibitors and two drugs entacapone and tolcapone are important in this category. In this video we will see how they act whether they effect metabolism of either levodopa or dopamine to produce benefit in Parkinson disease.
Hi today we will discuss about comt inhibitors catechol oh methyl transferase inhibitors what is comt comt is called as catechol whoa methyl transferase enzyme and this enzyme is response for the metabolism of this catechol amides for example if we take a structure like this is the top of mine and this is the norepinephrine and this is the epinephrine if you
Observe all these they’re having a common structural moiety which is nothing but the catechol structure and these mediators are hanging the catechol ring with an amine side chain so they are called as catecholamines so comt can tackle whoa methyl transferase enzyme can produce the metal balls off these catecholamines for example let us indicate the catechol moiety
Like this and the sidechain is indicated by r and we can start the numbering from the sidechain one two three and four so now in this catechol we can observe the which groups are present at the third and fourth positions and hear the comt enzyme is going to attack the voyage group at the third position so by action of this comt enzyme the voyage group is going to
Be converted into whoa ch3 group that is a methoxy group so comt kat carbo methyl transferase enzyme will convert the three voyage group into three methoxy group in this way this enzyme will produce one of the metabolites which is nothing but the three methyl kat a call so in this metabolic reaction methyl group is going to be transferred to the catechol where
This methyl group is going to be donated by s adenosylmethionine by this the comt can convert the catechol into a non catechol today let us see in this video how the inhibitors of the comt enzyme commonly known as comt inhibitors are useful in the treatment of markinson disease and how they are acting in this particular neurodegenerative disorder and how they are
Going to be given and what are the possible side effects now let us go with this comt inhibitors comt inhibitors can be identified by their suffix their having a common suffix like the cap on we have two drugs in this category like the nt capone and tol capone these two drugs are chemically belonging to category of nitro cata calls so let us start with the tall
Cap on tall capone is hanging their structure like this and you can observe one of the ring system here this is a cat a call with a nitro group a decently present so this is nothing but the nitro cat a call and again if you observe on the other side again it is hang a phenyl ring with a methyl group that means it sangha para toland group jolene is present as a
Radical in the structure so within the name tall cap on that tyl indicates it sang that totally in yd and if you combine these two phenyl rings with a ketone they’re having one of the central ring that is a binge of phenol so tall cap on is in nitro cat a call on the other side designed that tolan moiety and chemical it is also a benzophenone derivative and if we
Give the naming to this ring because both of the phenyl rings are not similar we can call it as methanol this mithran is attached with the two phenyl rings so if we give that name ring to the one of the phenyl ring this is 1 2 3 4 & 5 so it is hanging the third push and fourth question dye hydroxy group so three four dihydroxy and fifth position nitro group so
Five nitro and which is attached with the finance of five nitro phenol so 3/4 a hydroxy finite row phenol ring is going to be attached on the one side of the methanol and in the on their side it is on the parameter l phenol otherwise we can also write for methyl phenyl so that is the name of this tall cap on tall cap on is a nitro cat a call with a tolan moiety
And chemically it is a benzophenone derivative now let us go with the n take upon n take upon is hang the structure like this again you can observe the same ring system so it is also hang the nitro catechol moiety and if we give the name for this endeca porn here we have to identify the principle function group as de mi so we have to start the numbering from the
Amide so this is 1 2 & 3 so it’s having the proper num id but it is having a double bond at the second and third position so it can be represented as probe to in amide so it is a 2 propene amide and at the first position nitrogen is hanging that tighter group so n and diethyl and second position cyano group is there and third portion what is the group present
So third portion in deciding the nitro catechol moiety which can be represented as 3 4 dihydroxy and finite row phenol just like in the tol kapaun so this is the complete name of the n take a poem so if we see the tall cap on and n take upon both our hang the same structural moiety nitro cat a call now let us see how these drugs are going to act and how they are
Useful in the treatment of parkinson disease these comt inhibitors are used as add-on therapy that means these drugs are not used alone particularly these drugs are given along with the leo tapa in order to increase its action so now what we can control whether the comt inhibitors are going to acting on the levodopa otherwise the comt inhibitors are going to acting
On the top of mind because the leawood opera is having the structure like this and dopamine is having the structure like this so if we observe both of these structures are having the catechol moiety that means the comt which is the catechol whoa methyl transferase enzyme can produce the metabolic pathway or dopa as well as the dopamine now how these comt inhibitors
Are working whether they are inhibiting the mandible of the levodopa otherwise they are inhibiting the metal volume of the dopamine so let us see it in detail so let us start with the effect of the comt inhibitors on the dopamine metabolism the dopamine which is one of important catechol a mine and which is important for controlling the motor functions and when
These dopamine levels are going to fall within the central nervous system it produces a parkinson like symptoms so this dope mind can be metabolized into one of the metabolite dog-pack dihydroxy phenol istic acid by one of the important enzyme maho be enjoying this mawa b enzyme along with n the range i’m all dehyde dehydrogenase enzyme will convert the dopamine
Into the door pack that is a dihydroxy phenylacetic acid then this door pack can be metabolized by the comt enzyme the catechol home methyl transferase enzyme so that it is going to be converted into hv a homo vanilla cassatt in this way dog men can be metabolized by two important enzymes mobe enzyme as well as comt enzyme and here in this metabolic energy can
Act otherwise comt can also act and both of these enzymes are involved in the conversion of the dopamine into homo vanilla cassie and here mawa b enzyme is going to be inhibited by psyllid zeeland which is again used in the treatment of parkinson’s disease and comt is going to be inhibited by comt inhibitors which are indicated by the suffix cap on so cap on drugs
Are going to inhibit the comt enzyme so in this way comt inhibitors can inhibit the meta bosma of the dopamine within the brain but this is not the main mechanism of the comt inhibitors because even we block the comt still the dopeman can be metabolized by the mohave enzyme so inhibition of the metabolism of the dog mine is not the main mechanism involved behind
The action of the comt inhibitors in the treatment of parkinson disease as already we have discussed comt inhibitors are not given alone and they are given along with the levodopa so their main action depends on the innovation of the metabolism of the levodopa so now let us see what is the effect of the comt inhibitors on the levodopa meatball djem suppose these
Are cns and this is the periphery and between these two a strict border is present which we call the blood-brain barrier so this blood-brain barrier is going to allow the lipophilic drugs only levodopa is having a some special carrier by which it can be entered into the cns so levodopa is going to be transported with an amino acid carrier so that the levodopa can
Enter into the cns where the levodopa can be metabolized to produce the dope of mind by one of the enzyme the appa decarboxylase enzyme ddc in this way levodopa can increase the dopamine levels within the central nervous system which can improve the symptoms in the parkinson disease but here one of the important aspect is that the levodopa should be entered into
The cns but at the same time levodopa can be metabolized within the periphery by the two enzymes one is that dd c and there is a co empty so here we are going to focusing on the enzyme comt levodopa can be converted into oh metal neo dopa by one of the enzyme comt catechol whoa methyl transferase enzyme by this metabolic on the liver dope is converted it’s made
Up like like the o methyl levodopa but this metabolite is then going to inhibit the entry of the levodopa by competing with the same transporter so whenever the wahpeton levodopa levels are going to increase in the periphery it will inhibit the entry of the nevada pi into the cns so here comt inhibitors play an important role comt inhibitors are going to inhibit
The peripheral meta bottom of the levodopa so it is not converting to o methyl evo dopa which is going to interfere with its absorption into the cns in this way comt inhibitors can increase the permeability of the nevada pi into the cns where it can be converted into dope wine and thereby it can increase the dopamine levels within the cns and interestingly the
Cmt in witters can also act at the cns level so levodopa can also be attacked by the same enzyme comt which is present within the cns so again this enzyme is going to convert the leeward 0.20 methyl neo top of it in the cns this enzyme is inhibited by one of the drug toll kept on so toll kept on is can only show the activity at the center level whereas nt capone
Cannot show its activity because nt capone cannot cross the blood-brain barrier so action at the central level is not again the main mechanism but action at the peripheral level is main the mechanism of the comt inhibitors in this way what we can control that see why mt inhibitors are going to inhibit the meta bosma of the leo dope at the periphery thereby they
Can increase the the entry of the neodo point into the cns now let us see effect on on of effects of the leo tapa so levodopa which is present in the periphery it should cross the blood-brain barrier and should enter into the cns so centre levels of the neo dope are very important to show its action on the parkinson disease but the central levels of the neo dopa
Can be reduced and when these levels are going to fall a certain precipitation of parkinson symptoms like the rigidity and tremor can be observed in the patients so this effect where the effect of the leo dope is not present we can call off fa and whenever the levels of the leo dope are going to be raised the symptoms can be improved which we can call on effect so
By the fluctuations of the leawood upper levels centrally on of effects of the levodopa can be produced so how can we minimize this on of effects as we have seen leo topper is going to be metabolized into ohm italy would offer by the comt enzyme within the periphery so if we block this peripheral metabolism of the comt by the comt inhibitors then we can increase the
Li would open entry into the cns and we can minimize the fluctuations of the nevada upper levels within the cns so in this way comt inhibitors not only increase in action of levodopa they are going to minimize the honor of effects of the leeward opa so that’s why these drugs are given along with the levodopa and what are the initial doses with the comt inhibitors
So here the nd capone is initially used at a dose of 200 mg and told capone is used at a dose of 100 mg and these drugs are not used alone and they are given along with the dose of the levodopa what are the side effects the common side effects like that diarrhea and nausea can be observed and an the important side effect is that dyskinesia this ganesha is not the
Side effects related to the comt inhibitors but it is one of the side effects related to the levodopa but whenever these drugs are combined dyskinesia can be increased because these drugs are going to increase of the neodo power within the cns so dyskinesia is going to be produced because of the enhanced effects of the levodopa and other side effects include
That dizziness fatigue and anxiety that can be observed with the comt inhibitors toll capone is one of the drug which can cross the blood-brain barrier at the same time it also have some activity on the hepatic system so toll kept on can produce the fulminant liver failure so whenever this drug is going to be given it produced some hepatotoxicity due to this
Hepatotoxicity this drug is used under extreme conditions in combination with the labour appa even this drug is going to show it’s activity on the central comt enzyme but still hepatotoxicity is one of the limitation of this toll kept on so that’s about the comt inhibitor comt inhibitors like the enttec opponent ole capone are chemically belonging to the nitro
Canticles and these drugs are going to inhibit the one of the important enzymes comt cata calvo methyl transferase enzyme this enzyme is going to attack the catechol related drugs and it is going to convert the three boys group into three methoxy group here both the levodopa as well as dopamine are the catechol substances so that comt can metabolize both of these
But here the sibo empty inhibitors are going to inhibit the meta bosma of the levodopa thereby they can increase the levodopa levels within the cns within the periphery levodopa can be converted to ou methylated appa which will prevent the entry of the neo tapa by competitive inhibition for the amino acid transporter so comt inhibitors are going to inhibit this
Peripheral metabolism thereby they improve the entry of the levodopa within the central nervous system so that’s about the comt inhibitors and if you like this video please subscribe to our channel thank you for watching this video
Transcribed from video
COMT inhibitors || In Parkinson disease By egpat
