ALKYL HALIDES

GANGLIONIC BLOCKERS AND NEURO MUSCULAR BLOCKERS

GANGLIONIC BLOCKERS AND NEURO MUSCULAR BLOCKERS
GANGLIONIC BLOCKING AGENTS
The Ganglionic blocking agents are drugs which act by competiting with Acetyl choline (Ach) from the cholinergic receptors present in the autonomic post ganglionic neurons.
Since the ganglia of both the sympathetic and parasympathetic nervous systems are cholinergic, these drugs interrupt the outflow through both system.
They are used mostly for their interruption of the sympathetic outflow in hypertension, vasopastic disorders and peripheral vascular disease. Thus lowering the B.P and increasing the peripheral blood flow.
CLASSIFICATION
Based on the mechanism these are classified as follows.
1.By Interfering with Ach release - Triethyl choline, Hemicholinium
2. By interference with post synoptic action of Ach - Eg : Hexamethonium
3. By prolonged depolarization - Eg : Nicotine

NEURO MUSCULAR BLOCKING AGENTS
Agents which blocks the transmission of Ach at the motor end place are called neuromuscular blocking agents. They are used in surgical anesthesia as adjuvant to relax the skeletal muscle.
CLASSIFICATION
1.Natural Compounds – Eg : Tubocurarine chloride, Metocurarine iodide, Pancuronium bromide.
2. Synthetic Compounds - Eg : Gallamine triethiodide, Decamethonium bromide, Pipecuranium bromide, Vecuronium bromide.
Tubocurarine chloride Synthesis

SAR for Neuro muscular blockers

1. The drugs have quarternary ammonium group for good activity.
2. The type of alkyl group present in quarternary ammonium group determines the charge distribution and binding characters.
3. Non depolarizing drugs are bulky and more rigid than depolarizing drugs.
4. As the strerric hindrance to receptor increases, the potency decreases. L-tubocurarine is less potent than d-tubocurarine.
5. The depolarizing agents (Eg-Decamethonium) have a more flexible structure that enable bond rotation.
6. The distance between quarternary ammonium groups can vary up to the limit of maximal bond distance usually 1.0 ± 0.1 nm.

MECHANISM OF ACTION
Neuro muscular blocking agents can block the neuro muscular transmission by

• Inhibiting acetyl choline synthesis
• Inhibiting Ach release and inhibit calcium entry have neuromuscular block.
  Interfering with the post synoptic action of Ach.
• Non depolarizing blocking agents act by competitive antagonism at Ach receptos of the end plate and these largely accounts for their action.

CHOLINERGIC BLOCKING AGENTS

CHOLINERGIC BLOCKING AGENTS CHOLINERGIC RECEPTOR ANTAGONISTS (or) ANTI SPASMODICS
The anti cholinergic drugs are agents that inhibit the effect on Acetyl choline (Ach) released from post ganglionic parasympathetic nerve endings. They block muscarinic action of Ach including smooth muscle contraction and exocrine gland secretion. Because of the ability to relax smooth muscles, they are also referred as antispasmodics. The cholinergic blocking agents that have high affinity to the receptors may decrease the no. of available free receptors and the efficiency of the endogenous neuro transmitter like Ach. Anti muscarinic drugs act by competitive antagonism of Ach binding to muscarinic receptors.

CLASSIFICATION

1.Solanaceous alkaloids and Analogues - Atropine Sulfate, Hyoscyamine sulfate, Scopalamine HBr, Homatropine HBr, Ipratropium bromide.

2. Amino alcohol esters - Cyclopentolate. HCl, Clidinium bromide, Dicyclomine HCl, Glycopyrrolate, Methanthelin bromide, Propanthelin bromide, Mepenzolate.

3. Amino Alcohols- Biperidine HCl, Procyclidine HCl

4. Amino alcohol ethers Benztropine mesylate, Orphenadrine

5. Amino amide - Tropicamide, Isopropamide iodide

6. Miscellaneous - ethopropazine.

Atropine

Clidinium bromide Biperiden
SAR FOR CHOLINERGIC BLOCKING AGENTS

1. Anti cholinergic compounds has some structural similarity to acetyl choline but contain additional substituents which enhance their binding to cholinergic receptors.
2. R- may be hydroxy alkyl, alkyl, cycloalkyl or heterocyclic group for good anti cholinergic activity.
3. The nitrogen is tertiary atom which contains alkyl group not larger than butyl for effective antagonist activity.
4. The acyl group is always larger than acyl group in acetyl choline for good activity.
   Hydrophobic substituents increase the affinity to binding the receptors and have good antagonist property.
5. The presence of free hydroxyl or carbamide is also important for hydrogen bonding with receptor.
6. Naturally occurring l-hyocyamine is more active than d-isomer.

MECHANISM OF ACTION
The cholinergic blocking agents are competitively inhibit the cholinergic receptors and prevent the binding of acetyl choline to the receptors due to the size of acyl group through ‘umbrella effect’.
The large group (alkyl or aryl) present in cholinergic blocking agents increase the affinity of the blocking agent and also block the approach of acetyl choline to the receptor.

CHOLINERGIC DRUGS AND RELATED AGENTS

CHOLINERGIC DRUGS AND RELATED AGENTS
The autonomic nervous system (ANS) is composed of two divisions sympathetic and parasympathetic. Acetyl choline serves as a neuro transmitter at both sympathetic and parasympathetic pre ganglionic nerve endings.
Cholinergic agents are drugs that either directly or indirectly produce effect similar to acetyl choline (Ach). The neurotransmitter of pre ganglionic neuron is acetyl choline and post ganglionic neuron is nor adrenaline in sympathetic system. Acetyl choline is the neuro transmitter of all pre and post ganglionic neurons of parasympathetic system.
Cholinergic receptors
There are two types of cholinergic receptors on the basis of their ability to be bound by the naturally occurring alkaloids nicotine and muscarine are called nicotinic receptors and muscarinic receptor.
1. Nicotinic receptors
Nicotinic receptors are coupled directly to ion channels and mediate very rapid responses when activated by acetyl choline. These receptors are selectively activated by nicotine and blocked by tubocurarine or hexamethonium. These belongs to ligand -gate ion channel receptors and acetyl choline serve as a gate keeper by interacting with the receptor to modulate passage of ions, principally K + and Na + through the channel. Their activation causes opening of the channel and rapid flow of cation resulting depolarization and generation of action potential.
Sub types : - There are two types
N1 nicotinic receptors - These are present in neuromuscular junction. They are blocked by succinyl choline, d – tubocurarine and decamethonium and stimulated by phenyl trimethyl ammonium.
N2 nicotinic receptors - These are found in autonomic ganglia. They are blocked by hexamethonium and trimethaphan but stimulated by tetra methyl ammonium and diethyl 4-phenyl piperazinium (DMPP).
2.Muscarinic receptors :
Muscarinic receptors play as essential role in regulating the functions of organs in ANS to maintain homeostasis of the organism. The action of acetyl choline on Muscarinic receptor can result in stimulation or inhibition of the organ system affected. Acetyl choline stimulates secretions from salivary and sweat glands, secretions contraction of the gut and constriction of the airways of the respiratory tract.
Sub types: - There are five types of receptors M1, M2, M3, M4 and M5.
1. M1 receptors : They are located in CNS, exocrine glands and autonomic ganglia. These are identified in sub mucosal glands and some smooth muscles. When stimulated M1 receptors cause gastric secretion.
2. M2 receptors : These are called cardiac muscarinic receptors because they are located in atria and conducting tissue of the heart. Their stimulation causes a decrease in the strength and rate of cardiac muscle contraction. M2 receptor activate K+ channels to cause hyper polarization of cardiac cells, resulting in bradycardia.
3. M3 receptors : These are referred to as “glandular” Muscarinic receptor, are located in exocrine glands and smooth muscles. Glandular secretions from lacrimal, salivary, bronchial, pancreatic and mucosal cells in GI tract are characteristics of M3 receptor stimulations.
4. M4 receptors : They are present in tracheal smooth muscle, when stimulated inhibit the release of acetyl choline.
Bio chemical effects of Muscarinic receptor stimulation :
Transmission of synapse involving second messenger is much slower compared with at synapses where ion channels are activated directly. The sequence of bio chemical events in this second messenger system begins with activation of the receptors by an agonist and involves the activation of G – proteins that are bound to a portion of the intracellular domain of the Muscarinic receptors.
G – Proteins consists of 3 sub units, α, β and γ. When the receptor is occupied, the sub unit which has enzymatic activity, catalyses the conversion of GTP to GDP (guanosine diphosphate) which can associate with various enzymes and ion channels. A single drug – receptor complex can active several G – protein molecules and each can remain associated with a target molecule.
Adenylate cyclase is a membrane enzyme is another target of Muscarinic receptor activation. The second messenger cAMP is synthesized with in the cell from adenosine tri phosphate (ATP) by the actions of Adenylate cyclase. The cAMP activate protein kinase which catalyze the phosphorylation of enzymes and ion channels, alter the amount of calcium entering the cell and thus affecting muscle contraction.
But muscarinic receptor activation causes lower levels of cAMP, reducing CAMP protein dependent kinase activating and relaxation of muscle contraction.
Stereo chemistry of acetyl choline :
Acetyl choline exist in number of confirmations. Confirmational isomers of acetyl choline derived from rotation around – O –C – C –N – axis. Four of these confirmations are illustrated by Newman projection below.

CHOLINOMIMETIC (OR) PARASYMPATHOMIMETIC DRUGS
These are agents that mimic the action at Parasympathetic system.
CLASSIFICATION
1.Directly acting Cholinergic drugs (Agonist)
A) Choline Esters – Acetyl choline, Carbochol, Bethanechol, Methacholine.
B) Alkaloids - Pilocarpine
2.Indirectly acting Cholinergic drugs (Anti choline esterase)
A) Reversible Inhibitors – Physostigmine, Neostigmine, Pyridostigmine, Endrophonium chloride, Ambinonium chloride.
B) Irreversible Inhibitors – Pralidoxime chloride, Isoflurphate, Echothiophate iodide, Parathion, Malathion.
Carbochol
Carbochol - Synthesis

SAR for Cholinergic drugs SAR depends upon thr modifications of the following groups
I. Quaternary ammonium group :

1. The onium group is essential for intrinsic activity and contributes to the affinity to receptors.
2. Replacement of nitrogen with sulfur, arsenic or selenium produces less active compounds.
3. Primary, secondary or tertiary amines are less active than acetyl choline.
4. Replacement of methyl groups by ethyl or larger alkyl groups produces inactive compounds.
5. Compounds in which two methyl groups on nitrogen were retained and there were replaced by a larger alkyl groups were found to have considerable activity.

II. Modification of ethylene bridge :

1. Shortening or lengthening of the ethylene group that separates the ester group and ammonium group reduces muscarinic activity.
2. An α- substitution decreases nicotinic activity more extent.
3. Replacement of hydrogen atoms of ethylene bridge by alkyl groups are less active except when a single methyl group is placed either at α or β to the quaternary nitrogen atom.
4. The presence of methyl group α to nitrogen increases nicotinic activity ( Acetyl methyl choline) and β to nitrogen increases muscarinic activity (Methacholine)
5. Hydrolysis by acetyl cholinesterase is more affected by β – substitutions than α – carbon.

III. Modification of ester group :

1. The ester group of acetyl choline contributes to the binding of the compound to the muscarinic receptor.
2. When acetyl group is substituted by its higher homologues produce less active compounds.
3. When the acetyl group is replaced by a carbonyl (carbachol) has both muscarinic and nicotinic property.
4. Esters of aromatic or higher molecular weight acids possess cholinergic antagonist activity.
5. The methyl ester is rapidly hydrolyzed by cholinesterase.
6. When the terminal methyl group is replaced by – NH2 group, the resulting compound is potent cholinergic agent with both muscarinic and nicotinic activities.

ADRENERGIC ANTAGONISTS

ADRENERGIC ANTAGONISTS
SYMPATHOLYTICS (or) ADRENERGIC RECEPTOR BLOCKING AGENTS
Adrenergic antagonists are drugs that reduce the delivery of catecholamines to the adrenergic receptors by disrupting catecholamine synthesis, storage or release. They abolish the response to stimulation of sympathetic nerves.
These agents competitively antagonize the effect of the catecholamines at α and β adrenergic receptors.

CLASSIFICATION
I. α – Adrenergic blocking agents
1. Imidazolines – Tolazoline, Phentolamine
2. Beta Halo Alkylamines – Phenoxy benzamine, Dibenamine
3. Quinazolines – Prazosin, Terazosin, Doxazosin
4. Ergot Alkaloids – Ergotamine, Ergosin, Ergocrystin, Ergocriptine.
5. Miscellaneous – Yohimbin, Methy sergide
II. β – Adrenergic blocking agents
1. Aryl ethanolamines – Isoproterenol, pronethalol, Dichloro isoproterenol
2. Aryloxy propanolamines – Propranolol, Practalol, Metaprolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol.
III. Both α and β – Adrenergic blocking agents
Labetalol, Carvedilol.

I. α – Adrenergic blocking agents

Synthesis

Quinazoline Derivatives
Ergot alkaloids

II. β – Adrenergic blocking agents

These drugs block the effects of Endogeneous and exogeneous catecholamines. These drugs slow the heart rate and decrease the force of contraction. They competitively inhibit β – Adrenergic receptors. These are also used in the treatment of hypertension, arrhythmiasis, coronary artery disease and open angle glaucoma.

Practolol
Synthesis of Acebutolol

Other Beta blockers

III. Both α and β – Adrenergic blocking agents
Carvedilol

SAR for Beta blockers

1. The O-CH2 group between aromatic ring and the ethylamino side chain is responsible for the antagonistic property.
2. Replacement of catechol hydroxyl group with chlorine or phenyl ring retains the beta blocking activity.
3. N,N- di substitution decrease beta blocking activity. Activity is maintained when phenylethyl, hydroxyl phenyl ethyl or methoxy phenyl ethyl groups are added to amine as a part of molecule.
4. The two carbon side chain is essential for the activity.
5. Nitrogen atom should be of secondary amine for optimum beta blocking activity.
6. The carbon side chain having hydroxyl group must be S- configuration for optimum affinity to beta receptor.(Ex- Levobunolol, Timolol)
7. The aryloxy propanolamines are more potent than aryl ethanolamines.
8. Replacement of ethereal oxygen in aryloxy propanolamines with S, CH2 or N-CH3 is decreased the beta blocking activity.
9. The most effective substituents at amino group is isopropyl and tertiary butyl group.
10. The aromatic portion of the molecules could be varied with good activity.
11. Converting the aromatic portion to phenanthrene or anthracene decrease the activity.
12. Cyclic alkyl substituents are better than corresponding open chain substituents at nitrogen atom of amine.
13. Alpha methyl group at side chain decrease activity.

Mechanism of action

1. These drugs competitively inhibit the adrenergic receptors.


2. Beta antagonists are invariably employed in the treatment of essential hypertension and cause an effective decrease in BP by exerting direct effect on heart and blood vessels, minimizing sympathetic outflow from CNS and affecting the rennin-angiotensin- aldosterone system.


3. Some drugs like propranolol precipitate an asthmatic attack by antagonizing beta-2 receptors in bronchial smooth muscle and give rise to sudden contraction of bronchial smooth muscle.

SYMPATHOMIMETIC AGENTS

SYMPATHOMIMETIC AGENTS

Sympathomimetic drugs are agents which stimulate the sympathetic or adrenergic nerve by mimic the action of Nor epinephrine or indirectly by stimulating the release of Nor epinephrine.

Adrenergic Receptors
Sympathomimetic or Adrenergic drugs exert their effects by direct action on adrenergic receptors. There are two types.
1. alpha-Adrenergic receptors 2. beta- Adrenergic receptors

1. alpha-Adrenergic receptors
alpha-Adrenergic receptor sites have three parts
i) Anionic site(Phosphate) which binds with +ve ammonium group.
ii) One hydrogen binding area
iii) One flat area for aromatic ring binding.
Nor epinephrine activates primarily alpha-Adrenergic receptors

alpha-Adrenergic receptors have two types
a) alpha-1-Adrenergic receptors- which are found in smooth muscles of iris, arteries, arterioles and veis. It exerts their effect on post synoptic nerves. a1-Adrenergic receptor activation increase the influx of extracellular Ca2+ at calcium channels.
b) alpha-2-Adrenergic receptors – which mediate the inhibition of adrenergic neuro transmitter release. It exerts their effect on pre synoptic nerves. Activation of a2-Adrenergic receptors leads to a reduction in the catalytic activity of adenylyl cyclase.

2. beta- Adrenergic receptors
beta- Adrenergic receptor sites have the following parts
i) Anionic site which binds with +ve ammonium group.
ii) One hydrogen binding area
iii) One flat area for aromatic ring binding.
Epinephrine activates primarily b- Adrenergic receptor. b- receptor activation relaxes bronchial smooth muscles which cause bronchi of the lungs to dilate and also increases the rate and force of heart contractions.
beta- Adrenergic receptors are three types. They are
a) beta-1-Adrenergic receptors- found in myocardium where their stimulation increases the rate and force of myocardial contractions. They are located mainly in the heart, where they mediate the +ve inotropic and chronotropic effects of the catecholamines. They exhibit the agonist potency in the order of Isopreterenol > Epinephrine = Nor Epinephrine.
b) beta-2-Adrenergic receptors- found in bronchial and vascular smooth muscles where their stimulation causes smooth muscle dilatation and relaxation. They exhibit the agonist potency in the order of Isopreterenol > Epinephrine > Nor Epinephrine.
c) beta-3-Adrenergic receptors- They are expressed on fat cells and their stimulation causes lipolysis. They are located on brown adipose tissue and is involved in the stimulation of lipolysis. They exhibit the agonist potency in the order of Isopreterenol = Nor Epinephrine > Epinephrine.

Classification of Adrenergic Drugs
1.Direct acting Adrenergic Agonists
They are bind and activate a1, a2, b1, b2 receptors
Examples – Nor Epinephrine (binds with a1, a2, b1, receptors), Epinephrine (binds with a1, a2, b1, b2, receptors), Dopamine (with a1, a2, b1, , receptors), Xylometazoline, Phenyl ephrine, Methoxamine, Isoprenaline, Salbutamol.
2. Indirect acting Adrenergic Agonists
They produce Nor Ephidrine (NE) like actions by stimulating NE release, preventing its reuptake and thus its inactivation.
Example – Tyramine
3.Dual acting Adrenergic Agonists
These agents act as direct and indirect adrenergic agonists. They binds to adrenergic receptors and stimulate NE release.
Example – Ephedrine, Amphetamine, Mephentermine.

Chemical classification
1.Phenyl ethylamines and related compounds
Adrenaline, Nor Adrenaline(NE), Dopamine, Phenyl ephrine, Methoxamine, Methyl dopa, Isoproterinol(Isoprenaline), Salbutamol, Terbutaline, Dobutamine, Amphetamine, Ephedrine, Pseudo Ephedrine, Ritodrine, Salmeterol
2. Imidazoline derivatives
Naphazoline, Tetrahydrazoline, Oxymetazoline, Xylometazoline, Clonidine.

1.Direct acting Adrenergic Agonists
A. Endogenous Catecholamines

B. alpha-Adrenergic receptor Agonist

Clonidine Imidazolines C. b-Adrenergic receptor Agonist

Bitolterol D. Both a and b-Adrenergic receptor Agonist

2. Indirect acting Adrenergic Agonists

3.Dual acting Adrenergic Agonists

Ephedrine
SAR for Adrenergic Agonists

General structure

SAR for sympathomimetic drugs are discussed in the following category.
A). Substitution in the Phenyl ring system

1. The receptor selectivity of the drugs depends on the substituent at aromatic ring , a,b- Carbon and Amino group.


2. The maximal sympathomimetic activity shown by substitution of hydroxyl group in M and P position of aromatic ring.


3. The amino group should be separated from the aromatic ring by two carbon atoms for optimal activity.


4. The naturally occurring Nor Adrenaline has 3’,4’-dihydroxy benzene ring active at both a and b-Adrenergic receptors.


5. The dihydroxy substitution at 3’,4’ position(Ex-Metaproterinol) gives good oral activity and selectivity for b2-Adrenergic receptors.


6. Ther substituents like3’-hydroxy methyl (albuterol), 3’- trifluoro methyl, 4’ amino, 5’ chloro (Mebuterol) have good oral activity.


7. One hydrogen bonding group is essential at the 4’ position for beta activity and 3’- OH substitution for Alpha activity.

B). Substitutions at Nitrogen (Amino group)

1. The presence of amino group is important for direct agonist activity.


2. Primary and secondary amines are more potent direct acting agonist than tertiary amine.


3. Size in alkyl group of nitrogen increases, a-recptor agonist activity decreses and beta-receptor agonist activity increases (Ex-Isoproterenol).


4. N-substitution also provides selectivity for different b-receptor sub types. Large t-butyl group have selectivity to b2 receptor (Ex-Colterol). Ritordrine with large P-Hydroxy phenyl ethyl substitution is a aelective b2 agonist .


5. Nitrogen in the part of heterocyclic ring such as imidazoline possess anti hypertensive property.

C). Substitutions on Carbon in the side chain

1. There are two carbon atoms a and b to nitrogen function. Small alkyl groups such as methyl or ethyl present in the a-carbon, an ethyl group at this position diminish the a-activity for more than b-activity.


2. The presence of a-alkyl group increases the duration of action by making the compound resistant to metabolic deamination by MAO.


3. Maximal direct activity in a-methyl nor adrenaline in the erythro enantiomers.
   b- carbon has hydroxyl group in the (R) absolute configuration for maximal direct activity.
   

Mechanism of Action

1.For Directly acting Sympathomimetics
They act through complexation with specific receptors. For the activation of b-receptor phenolic hydroxy group in meta position of aromatic group and an alcoholic hydroxyl group in b-position of side chain and an amine with bulky group.

2.For InDirectly acting Sympathomimetics
They act either by releasing catecholamines mainly norepinephrine from storage granules in the sympathetic nerve terminals or through inhibition of nor adrenaline uptake at the neuronal membrane.

3. Sympathomimetics of Mixed action
They act by both mechanisms described above.

DRUGS ACTING ON ANS

DRUGS ACTING ON ANS
The drugs acting on the autonomic nervous system is known as Autonomic drugs. They are mainly classified as
1. Adrnergic drugs 2. Cholinergic drugs

ADRENERGIC NEURO TRANSMITTERS
Adrenergic nerves release the neurotransmitters like Nor Epinephrine(Nor Adrenaline), Epinephrine(Adrenaline) and Dopamine.

Structure and Physico chemical Properties:

1.Nor Epinephrine(Nor Adrenaline)

It is a neurotransmitter of post ganglionic sympathetic neurons. As a result of sympathetic nerve stimulation, it is released from sympathetic nerve endings in to the synoptic cleft, where it interacts with specific pre synoptic and post synoptic Alpha and beta adrenergic receptors. It has chiral carbon and exist as enantiomeric pair of isomers.

2.Epinephrine(Adrenaline)

It is not released from nerve endings, but synthesized and stored in the adrenal medulla, from which it is released in to the circulation. Epinephrine is also biosynthesized in certain neurons of the CNS. It belongs to the chemical class of substances known as catecholamines. They are easily oxidized in the presence of air or other oxidizing agents. So they are stabilized by anti oxidants such as ascorbic acid or sodium bi sulphite. It has chiral carbon and exist as enantiomers. Catecholamines are polar substance that contain both acidic(Phenolic -OH) and basic(Aliphatic amine) has pKa values 8.7 and 9.9.

3.Dopamine

It is a neurotransmitter in the basal ganglia of CNS. Dopamine b- hydroxylase enzyme converts dopamine in to nor epinephrine. The enzyme is not presnt in dopaminergic neuron. Hence it remains in original form to carry out the function of neuro transmitter.

Bio synthesis of neuro transmitters

The biosynthesis of catecholamines, Dopamine, Nor epinephrine and Epinephrine involves a sequence of enzymatic reactions.
Catecholamine biosynthesis takesplace in adrenergic and dopaminergic neurons in CNS, in sympathetic neurons of the ANS and in the adrenal medulla.
The aminoacid L-Tyrosine serves as the precursor for the catecholamines. It is acted by tyrosine hydroxylase to form L-dihydroxy phenyl alanine(L-dopa). The second step is the decarboxylation of L-Dopa to dopamine by L-aromatic aminoacid decarboxylate. Then this dopamine is hydroxylated by b- Mono oxygenase in presence of Cu2+ to give Nor epinephrine.
The bio synthesis is represented as follows.

Metabolism
The actions of adrenaline and nor adrenaline are terminated by the following three process.
Reuptake in the nerve terminal
Dilution by diffusion from the junctional cleft and uptake at non neuronal sites.
Metabolic transformation.
Two enzymes namely mono amino oxidase (MAO) and Catechol-O-Methyl Transferase (COMT) are important for the biotransformation of catecholamines. These enzymes are distributed through out the body.