chapter 1 adrenergic drugs final

Conceptual Medicinal Chemistry Adrenergic & Anti-Adrenergic Drugs

Chapter 1

Adrenergic & Anti-Adrenergic

Drugs

The branch of autonomic nervous system in which, norepinephrine (NE) is the neurotransmitter

between the nerve endings & the effector muscles is known as adrenergic nervous system.

Adrenergic drugs are chemical agents that exert their principle pharmacological & therapeutic

effects by either enhancing or reducing the activity of various components of sympathetic

divisions of ANS. In general, substances that exert effects similar to the stimulation of

sympathetic activity are known as sympathomimetics or adrenergic stimulants, while drugs

responsible for reduction in sympathetic activity are known as sympatholytics, anti-adrenergic

or adrenergic blocking agents.

Adrenergic Neurotransmitter

NE is the neurotransmitter of post-ganglionic sympathetic neurons. NE is synthesized & stored

in granules inside the nerve endings. It is liberated into the synapse during the depolarization in

quanta. Then, it migrates across synapses & binds to its

receptors on the target organs. Another endogenous

adrenergic receptor agonist is epinephrine (sym. adrenaline,

sympathin). This is synthesized & stored in adrenal

medulla & released into circulation from adrenal medulla.

Adrenaline is not released from peripheral sympathetic

nerve endings like NE. So, sometimes epinephrine is

referred to as neurotransmitter.

Both adrenaline & noradrenaline are chemically catecholamines (CAs). These compounds are

highly susceptible towards aerial & photo oxidation forming ortho-quinone compounds, which

on further reaction produce highly colored compounds. So, they are stored with antioxidants

such as ascorbic acid or sodium bisulphite in dark colored container. CAs are amphilic in nature

due to presence of acidic catecholic groups & basic amino group. At physiologic pH (7.4),

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cationic form predominates (95%), followed by zwitter-ionic form (3%) & non-ionized form

(2%). This accounts for high water solubility of these compounds as well as other CAs such as

isoproterenol.

Biosynthesis of catecholamines (Fig. 1.1)

Catecholamines are biosynthesized in adrenergic & dopaminergic neurons of CNS & ANS &

adrenal medulla. Essential amino acid L-tyrosine serves as precursor of CAs. It is synthesized

from related amino acid phenylalanine in the liver by enzyme p-hydroxylase. Tyrosine is taken

up from circulation by adrenergic neurons & chromaffin cells. In axoplasm, tyrosine is converted

into L-3,4-dihydroxyphenylalanine (L-Dopa) by tyrosine hydroxylase (tyrosine-3-mono-

oxygenase), an Fe2+ containing enzyme that utilizes tetrahydrobiopterin as cofactor & requires

molecular oxygen. This is rate-limiting step. Adrenergic nerve stimulation activates kinase that

phosphorylates tyrosine hydroxylase & increases activity. NE decreases the activity of tyrosine

hydroxylase. This feedback inhibition is due to competition between CA product & cofactor,

pterin. L-Dopa is decarboxylated to dopamine (DA) by a cytoplasmic & broad substrate specific

enzyme, L-aromatic amino acid decarboxylase that utilizes pyridoxal phosphate as cofactor &

also found in liver & kidney. This DA is reached into vesicles from neuron. In vesicles, DA is

stereospecifically hydroxylated at β-carbon atom (-OH group has R-configuration) to form

norepinephrine (NE) by Cu++ containing enzyme, dopamine-β-hydroxylase (dopamine-β-mono-

oxygenase) that utilizes ascorbic acid as cofactor. Depolarization initiates vesicle fusion with

plasma membrane & finally NE is extruded into synaptic cleft along with ATP & protein

“Chromogranin”.

In adrenal medulla, NE is converted into epinephrine by N-methylation. N-methylation is

achieved by cytoplasmic enzyme ‘phenylethanolamine-N-methyl transferase (PNMT)’.

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PNMT is also

found in heart &

brain in small

amount.

Epinephrine is

transported into

storage granules of

chromaffin cells.

Storage of CAs:

In chromaffin cells,

NE is stored in the

form of a complex

with ATP (in ratio

of 4:1). This

complex is

adsorbed in a

protein

chromogranin.

Usually, each

vesicle in

peripheral

adrenergic neuron

containing about

6000-15000

molecules of NE. In

adrenal medulla,

NA thus formed

diffuses out in

cytoplasm, where it

is methylated by PNMT & converted into epinephrine. The cytoplasmic pool of CAs is kept

constantly by enzyme present in outer surface of mitochondria.

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Release of CAs

Depolarization of adrenergic neuron, triggers

transient opening of voltage gated Ca++ channels

leading to influx of Ca++. This influx triggers fusion

of storage vesicles with neuronal cell membrane,

leading to out flux of NE & other content of

vesicles into synapse through exocytosis.

Granules also contain peptides like enkaphalins or

neuropeptide γ also release their material

simultaneously. This release is modulated by

presynaptic inhibitory α2-receptors. (Fig 1.2)

Indirect acting sympathomimetics also induce release of NA, but they do by displacing NA from

the nerve ending binding sites & by exchange diffusion visiting amine carrier of uptake 1. This

process is not Ca++ dependent & not exocytotic.

Reuptake

The action of NE at adrenergic receptors is terminated by a combination of processes including

uptake into the neurons & extra neuronal tissues, diffusion away from synapse & metabolism.

Usually, primarily, action of NE is terminated by reuptake of CA at nerve terminals or recycling

through active transport uptake into presynaptic neuron. This process is termed as uptake 1. It

involves Na+/Cl- dependent transmembrane transporter having high affinity for NE. Upto 95% of

NE is removed from synapse by this process. This uptake can be blocked by cocaine & some

tricyclic antidepressants. Some amount of NE re-enters the sympathetic neuron & is transported

into storage granules by an H+-dependent transmembrane vesicular protein, where it is held in a

stable complex with ATP & chromogranin until sympathetic nerve activity or some other

stimulus causes it to be released into the synaptic cleft.

A less efficient uptake process, uptake 2 operates in a variety of other cells operates in a variety

of cells like glial, hepatic & myocardial cells. This process has low affinity for NE & operates in

higher concentration of NE. Actually it operates extraneuronal tissues.

NE taken into presynaptic neuron by uptake 1 is metabolized by a mitochondrial enzyme,

monoamine oxidase (MAO) & fraction of NE which escapes uptake 1 diffuses out of the synapse

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& is metabolized in extraneuronal sites by a cytosolic enzyme, catechol-O-methyl transferase

(COMT), that methylates the meta-hydroxyl groups.

Table1.1: Characteristics of Uptake1 & Uptake 2

S.No. Characteristic Uptake 1 Uptake 2

1.

2.

3.

4.

5.

6.

Transport of NE(in rat heart)

Vmax(nmol/gm/min)

Km

Specificity

Location

Other substrates

Inhibitors

1.2

0.3

NE > Adr > Iso.

Neuronal

Methylnorepinephrine,

Dopamine, 5-HT, Tyramine,

antiadrenergics

Cocaine, TCAs,

phenoxybenzamine

100

250

Adr. > NE > Iso.

Extraneuronal

NE, Dopamine, 5-HT,

histamine

Normetanephrine,

Phenoxybenzamine,

Steroid hormones

Metabolism (Fig. 1.3)

Monoamine oxidase (MAO), a mitochondrial enzyme (outer membrane) & catechol-O-methyl-

transferase (COMT), cytosolic enzymes are two principal enzymes involved in metabolism of

CAs. Both of these enzymes are distributed throughout body but higher concentration is found in

liver & kidney.

MAO leads to oxidative deamination of amino group attached to terminal C-atom of CAs,

producing aldehydes. There are two forms of MAO viz. MAO-A & MAO-B. Similarly, COMT

catalyses methylation of meta-hydroxyl group of a variety of catechol containing molecules.

COMT & MAO lack substrate specificity. They also further act on metabolites produced by

them.

NE is oxidatively deaminated by MAO to 3,4-dihydroxyphenylglycoldehyde (DOGPAL), which

is reduced to 3,4-dihydroxyphenylethyleneglycol by aldehydes reductase. This metabolite is

mainly released into circulation where it undergoes methylation by COMT in non-neuronal

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tissues to form 3-methoxy-4-hydroxyphenylethyleneglycol, which is further oxidized by alcohol

dehydrogenase followed by aldehydes dehydrogenase to 3-methoxy-4-hydroxymandelic acid

also known as vanillyl mandelic acid (VMA). VMA can be final product of several pathways of

NE metabolism. 3-Methoxy-4-hydroxyphenylethyleneglycol is its main precursor. At

extraneuronal sites such as liver, DOGPAL is mainly oxidized to 3,4-dihydroxymandelic acid by

aldehydes dehydrogenase. VMA is the final metabolite of NE & epinephrine, whereas dopamine

is excreted mainly as homovanillic acid (HVA). These products are usually conjugated with

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glucuronic acid before excretion in urine. Endogenous epinephrine is mainly excreted as

metaepinephrine & VMA.

Adrenergic Receptors & subtypes

Ahlquist was first to propose the existence of the two general types of adrenergic receptors in

mammals. He designated them as α & β receptors. Later postsynaptic α-receptors were referred

to as α1 (excitatory), while presynaptic as α2-adrenoceptors (inhibitory).

β-Adrenoceptors

Lands (1962) suggested β-receptors could also be subdivided into β1 & β2 subtypes. In 1984,

Arch et al. reported third β-subtype i.e. β3 in brown adipose tissue. The β1-receptors exhibit the

agonist potency in order isoproterenol > epinephrine = NE, while for β2-receptors potency order

is isoproterenol = NE > epinephrine.

β1-receptors are mainly distributed in heart, where they mediate positive inotropic & chronotropic

effects of catecholamines. They are also found in JG cells of kidney, where these are involved in

increase in rennin secretion. β2-receptors are mainly located on smooth muscles of the body,

where they cause relaxation producing effects like bronchodilation & vasodilatation. In liver, β2-

receptors promote glycogenolysis. β3 receptors are located on brown adipose tissue & stimulate

lipolysis.

Table 1.3: Differences between β1, β2 & β3-adrenoceptors

S.

No.

Characteristics β1 β2 β3

1.

2.

3.

4.

Location

Selective agonist

Selective antagonist

Potency of NA as agonist

Heart, JG cells in

kidney

Dobutamine

Metoprolol,

atenolol

Strong

Bronchi, blood

vessels, uterus,

g.i.t., urinary

tract, eye

Salbutamol,

terbutaline

ICI-118551, α-

methylpropranolol

Weak

Adipose tissue

BRL 37344

CGP20712A

Strong

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α-Adrenoceptors

α-Adrenoceptors are involved in control of CVS activities e.g., constriction of vascular smooth

muscle controlled by both postjunctional α1 & α2 receptors, though α1 action is predominant. In

heart, activation of α1 receptors results in selective inotropic response with little or no change in

HR.

Table 1.4: Differences between α1 & α2 receptors

S. No. Characteristics α1 α2

1

2.

3.

Location

Selective agonist

Selective antagonist

Post-junctional on effector

organs

Phenylephrine, methoxamine

Prazosin

Prejunctional on nerve

endings (α2A), also post

junctional in brain, pancreatic

β-cells, platelets &

extrajunctional in certain

blood vessels

Clonidine

Yohimbine, rauwolscine

Characterization of Adrenergic Receptors (Fig. 1.4)

Adrenoceptors are the members of a receptor superfamily of membrane spanning proteins

including muscarinic, serotonin & dopamine receptors. These are coupled to intracellular GTP-

binding proteins (G-protein). These receptors have a single polypeptide chain, looped back &

forth to cell membrane, sometimes with an extracellular N-terminus & intracellular C-terminus.

The seven transmembrane domains TMD1-TMD7 are composed primarily of lipophilic amino

acids arranged in α-helices connected by regions from loops on the intracellular & extracellular

faces of the membrane. The recognition sites for agonist/antagonists are located with the

membrane bound portion of the receptor. The binding site is located within a pocket formed by

the membrane-spanning region of the peptide.

All of the adrenoceptors coupled to their effectors system through G-protein, which is linked

through reversible binding interactions with third intracellular loop of the receptor region.

Actually, cytoplasmic region of the receptor interact with G-protein. Specifically, Asp113 in

TMD-3 of β2-receptor, an acidic residue that forms a bond (presumably ionic bond or a salt

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bridge), with the positively charged –NH2 group of CA agonist. Ser204 & Ser207 of TMD5 form

hydrogen bond

Table 1.5: Effects mediated by adrenoceptors subtypes

Predominantly α-receptors

(a) Medulla oblongata (α2)

(b) Blood vessels (α1)

Skin & mucosa

Cerebral

(c) Skin (α1)

Pilomotor muscle

Sweat gland

(d) Radial muscles of iris (α1)

(e) Salivary glands except parotid

(f) Sex organ, male

Predominantly β-receptors

(a) Heart (β1, α1)

SA node (β1)

Atria (β1)

AV node (β1)

Ventricles (β1)

(b) Bronchial muscles (β2)

(c) Skeletal muscle changes (β2)

(d) Skeletal muscle blood vessels (β2)

Both α & β-receptors

(a) G. I. Tract

Motility & tone (α2, β2)

Sphincter (α)

Pancreas

α2

β2

Reduction of BP & HR

Constriction

Constriction (slight)

Constriction

Slight constriction

Constriction (mydriasis)

Thick, viscous secretion

Ejaculation

Increased HR (positive chronotropic)

Increased contraction (positive inotropic)

Faster conduction

Increase contractility & conductivity, increased

automaticity (positive dromotropic)

Relaxation

Changes in contractility

Dilatation

Deceased

Contraction

Inhibition of insulin secretion

Stimulation of insulin release, glucagons secretion

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(b) Urinary bladder

Trigone (α)

Detrusor (β)

(c) Blood vessels

Coronary (α1, β2)

Pulmonary (α1, β2)

Abdominal viscera (α1, β2)

Renal (α1, β2)

Skeletal muscle (α1, β2)

(d) Adipocytes

α2

β3

(e) Liver (α1, β2)

(f) Uterus

α1

β2

(g) Leukocytes (β2)

(h) Platelets (α2)

(i) Kidney (mainly β1)

(j) Posterior pituitary (β1)

(k) Mast cells (β2)

(l) Nerve terminals

Adrenergic (α2, β1)

Cholinergic (α2)

Contraction

Relaxation

Constriction, dilatation


Constriction (mainly), dilatation



Inhibit lipolysis

Lipolysis

Glycogenolysis, neoglucogenesis, inhibition of

glycogen synthetase

Stimulation

Inhibition

Inhibits chemotaxis & lysosomal enzyme release

Platelet aggregation

Rennin release

ADH secretion

Inhibition of mast cells

Decrease release, increased release

Decrease release

with catechol meta & para-hydroxyl group, respectively of adrenergic agonist, while β-hydroxy

group of adrenergic agonist form hydrogen bond with side chain of Aspragine293 in TMD6 &

Phe290 interact with catechol ring. A disulphide bond is existing between Cys106 & Cys184 in

TMD4. Third intracellular loop connecting TMD5 & TMD6 is the site of linkage between

receptor & its associated G-proteins.

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Effector Mechanism of

Adrenoceptors

The adrenergic receptors, each are

coupled through the G-proteins to

the effector mechanism. Effector

mechanisms are proteins that are

able to translate the conformational

changes caused by activation of

receptor into a biochemical event.

β-Receptors (Fig 1.5)

All the three β-receptors are coupled

via specific G-protein (Gs) to the

activation of adenlyl cyclase, which

catalyzes the conversion of ATP into

camp. GDP binds reversibly with Gs

protein in absence of agonist.

Interaction of agonist to the receptor leads to conformational changes in Gs-protein, causing

decrease in its affinity for GDP with concomitant increase in affinity for GTP. GTP binds to αS-

subunit of Gs-protein, dissociates from receptor G-protein ternary complex & binds to &

activates adenylyl cyclase. The bound GTP is, then, hydrolyzed to GDP & the receptor-Gsprotein

complex returns to the basal state.

Intracellularly, secondary messenger cAMP activate protein ‘kinase’, which phosphorylates

specific proteins responsible for specific pharmacological actions. A class of enzymes known as

“phosphodiesterase”, which hydrolyse cAMP to AMP, terminating the action of cAMP.

Binding of adenylyl cyclase requires Mg++ complex in inner membrane of cell, which can be

inhibited by a number of nucleoside triphosphates & their analogs. They inhibit adenylyl cyclase

at Mg-ATP binding site. Other inhibitors include divalent inorganic ions, Li+, F- etc.

prostagladins PGE1 & PGE2 also stimulate adenylyl cyclase. Activation of phosphodiesterase

requires Ca++, so EDTA may inhibit the action of PDE. Other inhibitors include xanthines

(specially theophylline) & 1-methyl-3-isobutyl xanthine (MIX). Overall cascade is drawn in Fig.

1.5.

- 11 -

Fig 1.4: Binding sites for epinephrine on adrenergic

receptor


α-Receptors

Both the subtypes (α1 & α2) also belong to the superfamily of membrane receptors coupled with

G-proteins. The α1-adrenergic

receptor is coupled

‘Phospholipase C’ (PC) via

Gq-protein. PC hydrolyses

phosphatidyl inositol-1,4,5-

triphosphate (PIP3) to

secondary messengers

inositol-1,4,5-triphosphate

(IP3) & 1,2-diacylglycerol

(DAG). IP3 (water soluble)

stimulates the release of Ca++

from sarcoplasmic reticulum,

while DAG (lipid soluble)

activates ‘protein kinase C’

(pKC), an enzyme that

phosphorylates proteins.

α1-adrenergic receptor

activation also increases

extracellular Ca++ influx via

voltage dependent as well as

non-voltage dependent Ca++

channels. (Fig 1.6)

α2-adrenergic receptors are

coupled with Gi-protein,

which on activation by α2-

adrenergic agonists inhibits adenylyl cyclase leading to decrease in intracellular cAMP level.

Thus, activity of α2-adrenergic receptors is just opposite to that of β-receptors.

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Fig 1.5: Effector mechanism of action of β-receptors


Design of Drugs affecting Adrenergic Nervous System (Fig 1.7)

The multiple sites involved in activation of adrenergic nervous system suggest several

approaches to design the drugs to control its action. Among these are

1. Drugs that affect the biosynthesis of CAs.

2. Drugs that affect storage & release of CAs.

3. Drugs affecting the receptors i.e. agonists & antagonists.

4. Drugs affecting metabolism &/or removal of CAs from areas surrounding the receptors.

5. Drugs affecting the postsynaptic regulation of hormone action.

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Drugs affecting CA biosynthesis

Metyrosine: It is α-methyl derivative of tyrosine. It is a competitive inhibitor of tyrosine

hydroxylase, the first & rate limiting step of CA biosynthesis. However, it is used as a racemic

mixture. (-) isomer [posses inhibitory activity. It is used in

pre-operative management of pheochromocytoma. The

drug is excreted mainly unchanged in urine, due to very

low solubility in water. Crystalluria is a potential side

effect. It is supposed to be ideal drug for biosynthetic

inhibition of CAs.

Aromatic amino acid decarboxylase (step 2) may is

inhibited by α-methyldopa & carbidopa. Actually,

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carbidopa acts a as substrate for enzyme & is effective inhibitor because its rate of

decarboxylation is too much lower than that of methyldopa.

Dopamine hydroxylase can be inhibited by disulfiram (an antabuse) has non-specific action on a

number of oxidative enzymes. It is used in alcohol withdrawal due to having inhibitory activity

alcohol dehydrogenase.

Drugs affecting storage & release of CAs

Since stimulation of adrenergic system requires the release of NE (& other CAs) from its storage

sites & then from the neuron. Compounds affecting this release may effectively control organs

innervated by ANS.

Cocaine & reserpine deplete NE, epinephrine & serotonin from sites of storage. Reserpine

binds tightly to ATP driver monoamine transporter, leading to blockage of transport of CAs form

cytoplasm to storage vesicles. Thus, CAs are not released but metabolized by MAO. Reserpine is

metabolized by hydrolysis of ester functional group at position 18. it is used in the treatment of

hypertension. Diuretics, usually increases the efficacy of reserpine. Cocaine interferes with NE

uptake at neurons leading to increase in NE concentration at receptor.

Guanethidine & Guanadrel are neuronal blocking agents that prevent release of NE from

sympathetic terminals. These drugs enter in uptake 1 & accumulate in neuronal storage vesicles,

where they stabilize neuronal storage vesicle membrane & make them less responsive to nerve

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impulse. In these compounds, a guanidine moiety [NHC(=NH)NH2] is attached to either an

alicyclic or aromatic lipophilic group. Due to presence of very basic guanidine group (pKa > 12)

these compounds are protonated at physiological pH, so these are unable to cross blood brain

barrier. Guanethidine is absorbed incompletely after oral administration (3-50%) while guanadrel

is well absorbed (bioavailability 85%).

Guanethidine has half-life of 5 days, while

guanadrel has 12 hours. Both are partially

metabolized by liver. Both the drugs are

used as antihypertensive.

Bretylium tosylate (Bretylol) is another

neuronal blocking agent containing

aromatic quaternary ammonium moiety &

used as antiarrythymic agent.

Drugs Affecting Adrenoceptors i.e., Agonists & Antagonists

Adrenoceptor Agonists (Sympathomimetics)

Sympathomimetic agents produce effects resembling those produced by stimulation of

sympathomimetics nervous system. they may be classified as follow:

1. Direct acting sympathomimetics elicit sympathomimetic response by interacting directly

with adrenergic receptors.

2. Indirect acting sympathomimetics produce adrenergic effects by causing release from

adrenergic nerve terminals, but they do not act directly.

3. Mixed mechanism of action is also shown by some drugs.

(A) Direct Acting Sympathomimetics

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The parent structure of many of the sympathomimetics is β-phenylethylamine.

In general, for agonistic activity at adrenergic nerve, these are essential conditions:

(1) A phenylethylamine structure

(2) A 3-hydroxy substitution on the

ring, preferably a 3,4-dihydroxy

substitution (catechol) on the

ring.

(3) A β-hydroxyl group with proper

steric configuration at that

position.

(4) A small substitution (H, CH3,

CH2CH3) may be placed on the

catechol without affecting agonist

activity.

(5) The nitrogen atom must have atleast

one hydrogen.

Stereochemical Aspects

Direct acting sympathomimetics that exhibit

chirality by virtue of the presence of a β-

hydroxyl group (phenylethanolamine)

invariably exhibit high stereoselectivity in

producing their agonistic effect i.e. one

enantiomer is more potent than other

enantiomer. In NE & related compounds,

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enantiomer having (R)-configuration is

about 100 times more potent than (S)-

enatiomer. It is assumed for all the directly acting β-phenylethylamine derivatives structurally

resembling to NE, the more potent enantiomer should have conformation that results in

arrangement in space of the catechol group, the amino group & β-hydroxyl group in a fashion

resembling that of R(-)NE. This explanation of stereochemistry of NE is known as Easson-

Stedman Hypothesis, which is based on the presumed interaction of these three critic

pharmacophoric groups with three complementary binding areas on the receptors. (Fig 1.8)

Structure-Activity-Relationships of β-phenylethylamine derivatives

(I) R1, Substitution on Amino Nitrogen atom

The presence of amino group in phenylethylamines is important for direct activity. The

amino group should be separated from aromatic ring by two carbon atoms for optimal

activity. Both primary & secondary amines found in potent direct acting agonists, but tertiary

amino group reduce activity.

1) As the bulk of substitution on N-atom increases, the affinity for α-receptor decreases & for β-

receptor increases. For example, NE having hydrogen at N-atom is a potent β1-agonist & α-

agonist, epinephrine having methyl group at nitrogen atom is potent α, β1 & β2 agonist &

isoproterenol having isopropyl group on nitrogen atom is a potent β1 & β2 agonist.

- 18 -


Presumably, the β-receptor has a large lipophilic binding pocket adjacent to the amine

binding asparatic acid residue, which is absent in α1-receptors. If R1 becomes larger than

butyl group, than intrinsic activity is lost & then, respective compound becomes α1-blocking

activity. e.g. labetalol.

2) N-substitution provides the selectivity for different β-receptors, like N-tert-butyl substitution

enhances the β2-selectivity. e.g. N-tert-butylnorepinephrine (Colterol), prodrug is bitolterol,

is 9-10 times more potent at bronchial β2-receptors than cardiac β1-receptors. Large lipophilic

substitution on N-atom enhances β2-selectivity. e.g. formoterol, salmeterol, ritodrine etc.

3) Large substitution on N-atom gives MAO resistant compounds.

(II) R2 substitution, α to the basis nitrogen, Carbon 2

1) small ethyl or methyl substitution on -carbon of the ethylamine side chain reduces the direct

receptor agonist activity at both - & - receptors. Such substitutions slow metabolism by

MAO. Such compounds often exhibit enhanced oral effectiveness & greater CNS activity.

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2) An -ethyl group diminishes -activity for more than -activity affording the compounds as

ethylnorepinephrine & isothrine, a selective 2-agonist, while methyl substitution at this

position favors 2-selectivity like -methylnorepinephrine & methyldopa.

3) Another effect of -substitution is the introduction of new chiral center, which has the

pronounced effects on the stereochemical requirements for activity. For example, with -

methylnorepinephrine, it is erythro (1R,2S) isomer that possesses significant activity at 1-

receptors.

(III) R3, substitution on the aromatic ring

1) The natural 3’,4’-dihydroxy (catechol) subtitution ring provides excellent & receptor

activity, but catechol containing compounds have poor oral activity because they are

hydrophilic & readily oxidized by COMT & MAO.

2) 3’,5’-dihydroxy (resorcinol) substitution forms such compounds, which are not substrate for

COMT as well as MAO & have longer duration of action, good oral activity & better

selectivity at 2-receptors. e.g. resorcinol substitution in isoproterenol in place of catechol

produces metaproterenol, a 2-agonist. Another example on such compounds is terbutaline.

Metabolism of these compounds usually occurs by glucuronide conjugation.

- 20 -


3) Replacement of meta-hydroxyl group of catechol structure with a hydroxymethyl group also

provides 2-receptor agonist. E.g. albuterol (salbutamol), salmeterol, pirbuterol (having pyridine

ring in place of phenyl ring). Theses compounds are also COMT & MAO resistant & possesses

better oral activity.

4) Removal of p-hydroxy group from epinephrine provides phenylehrine, a selective 1-

agonist.i.e. removal of 4’-hydroxy group eliminates the -activity. Another example is

Metaraminol.

5) Removal of meta-hydroxyl group results in selective 2-receptor agonist like ritodrine

(Yutopar), Isoxsurpine & nylidrine.

- 21 -


6) 2’,5’-dihydroxy substitution in aromatic ring shows the selectivity for -receptors. e.g.

Metoxamine, a selective 1-agonist, but at higher concentrations it may exhibit -blocking

activity. Another example include Midodrine.

(B) Indirect Acting Sympathomimetics

Indirect acting sympathomimetics act by releasing endogenous norepinephrine. They enter the

nerve ending by the way of active uptake process & displace norepinephrine from its storage

granules. Certain structural characteristics tend to impart indirect sympathomimetic activity.

Some of them are following:

1) Like direct acting sympathomimetics, presence of catechol hydroxyl group enhances the

potency of indirect acting phenylethylamines, but is not mandatory.

2) The presence of -hydroxyl group decreases & -methyl group increases the effectiveness of

indirect acting sympathomimetics. e.g. amphetamine, S(+) enantiomer is used.

3) The presence of nitrogen substitution decreases the activity, while the substitutions larger

than methyl group rendering the compound inactive. Compounds with N-methyl group are

orally well active since they are MAO resistant. e.g. Mathamphetamine

4) Presence of tertiary amino group makes the compound inactive.

5) Phenyl moiety can be substited with either aromatic or cycloalkyl group e.g. Propylhexedrine

(Benzdrex), Tazolol. Propylhexdrine is used as a vasoconstrictor & nasal decongestant.

- 22 -


Other indirect acting sympathomimetics include Hydroxyamphetamine (Peredrine) & -methyl

derives of p-tyramine. Hydroxyamphetamine is used to dilate the pupil of eye for diagnostic eye

examination. It has some atropine like anticholinergic actions like mydriasis.

(C) Sympathomimetics with mixed mechanism of action

Ephedrine has mixed mechanism of action. The basic difference in activity is due the

stereochemistry of the carbons possessing -hydroxyl group & methyl group (carbon 1 & carbon

2 respectively). Due to two chiral atoms in ephedrine, there may be four enantiomer of

ephedrine. Racemic mixture of erythro (D) pair of enantiomer is known as “ephedrine”, whereas

racemic mixture of threo (L) pair of enantiomer is known as pseudoephedrine (-ephedrine).

This drug is obtained from alkaloids of Ephedra spp. Natural ephedrine is D (-) isomer having

(1R:2S) configuration & is the most active in all the four isomers, (1S:2R) enantiomer i.e. D (+)

ephedrine & (1S:2S) enantiomer i.e. L (+) pseudoephedrine usually have the indirect activity

& (1R:2R) enantiomer i.e. L(-) pseudoephedrine is inactive.

- 23 -


(1R:2S)D(-) ephedrine & (1S:2S)L(+) pseudoephedrine are not metabolized by MAO & COMT,

but they are p-hydroxylated & N-demethylated by CYP450 mixed function oxidase. Ephedrine

decomposes gradually & darkens when exposed to light. It is a strong base, pH >10.

Phenylpropanolamine (Propadrine) is similar to

ephedrine in structure except it has terminal primary

amine in place of secondary amine as in ephedrine. This

modification gives an agent that has higher vasopressive

action & lower central stimulatory action than ephedrine.

It is better nasal decongestant than ephedrine. It is orally active also.

Metaraminol (Aramine): 3-(2-amino-1-hydroxypropyl)phenol

It is structurally similar to phenylephidrine except it has terminal

primary amine & possess direct action on α-adrenergic neurons. It

is used parenterally as vasopressive in the treatment & prevention

of acute hypotensive state occurring with spinal anesthesia.

Description of Sympathomimetics

(A) Endogenous catecholamines

Dopamine: Three natural occurring catecholamines are dopamine, norepinephrine &

epinephrine along with norepinephrine & epinephrine used in the treatment of shock. It enhances

blood flow to kidney, enhancing glomerular filtration rate, Na+ excretion & inturn increases urine

output. The dilation of blood vessels produced by dopamine is the result of agonistic action on

D1-receptors. Dopamine also stimulates cardiac β1-receptors to increase cardiac output.

Dopamine intravenous (>10μg/kg/min) stimulates α1-receptors, leading to vasoconstriction & an

increase in arterial blood pressure.

Norepinephrine (Levophed): It has also poor oral bioavailability & is a good substrate for

MAO & COMT. Rapid metabolism causes short duration of action. It is used to maintain blood

pressure in acute hypotension resulting from surgical or surgical trauma, central motor

depression & hemorrhage. It is given intravenously.

Epinephrine (Adrenaline): It has stimulatory effects on both α- & β-receptors. Like other

catecholamines, it is also light sensitive because of catechol ring system. pink colour indicates

- 24 -


the presence of oxidative breakdown. It is inhibited by antioxidant like NaHSO3. as a free amine,

it is used as aqueous solution for inhalation. It is rapidly destroyed by alkaline solutions, metals

(Ca, Fe, Zn etc.), weak oxidizing agents & aerial oxygen.

Dipivefrin (Dipivalyl epinephrine, propine): It is prodrug of epinephrine that is formed by

esterification of catechol hydroxyl groups with pivalic acid. It is more lipophilic than

epinephrine, so it has more oral bioavailability. It penetrates eye better (so used in open angle

glaucoma) & reduces the doses w.r.t. Epinephrine. In cornea & anterior chamber, it is broken

down into epinephrine by esterase & it is less irritant than epinephrine.

(B) α1-Adrenergic Receptor Agonists

Phenylephrine (Neo-synephrine): 3-[1-hydroxy-2-(methylamino)propyl]phenol

Removal of 4’-OH group from phenylethylamine structure eliminates β-activity & enhances α1-

activity. Phenylephrine is a prototype drug for α1-agonists.

It is more potent vasoconstrictor than epinephrine &

norepinephrine. Oral bioavailability is good, it is

metabolized by MAO only, not by COMT due to lack of

catechol ring.

It is non-toxic & crosses blood brain barrier. It is used as nasal decongestant & to dilate the pupil

(in treatment of open angle glaucoma). It is also used in spinal anesthesia, to prolong anesthesia

& to prevent a drop in blood pressure during anesthesia.

Methoxamine (Vasoxyl): 2-amino-1-(2,5-dimethoxyphenyl)propan-1-ol

It is selective direct agonist. This drug is not substrate for COMT,

duration of action is longer than norepinephrine & is bioactivated

by O-demethylation to an active m-phenolic compound. It is

primarily used during surgery to maintain the adequate arterial BP,

especially in conjunction with spinal anesthesia. It does not

stimulate CNS.

- 25 -


Midodrine (Proamatine): 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide

It is N-glycyl prodrug of α1-selective agonist desglymidodrine. It is used as a vasoconstrictor in

the treatment of hypotension.

(C) α2-Receptor Agonists

Methyldopa (Aldomet): it is a prodrug of NE, which is not given as drug. Methyldopa (L-α-

methyl-3,4-dihydroxyphenylalanine) is a close structural analog of L-dopa & is a substrate for

the enzyme, L-aromatic amino acid decarboxylase. Methyldopa is converted into α-

methylnorepinephrine having (1R, 2S) configuration & acts selectively on α2-adrenoceptors in

CNS as same manner as clonidine.

Due to more hydrophilicity, they (α-methyldopa & α-methylnorepinephrine) are unable to cross

blood brain barrier. Α-Methylnorepinephrine replaces norepinephrine at the nerve terminals & it

has the intrinsic activity, so it can act as false neurotransmitter. It also decreases concentration of

dopamine, epinephrine & serotonin in CNS & periphery. It also decreases sympathetic outflow

& BP.

Methyldopa is used only by oral administration since its zwitterionic character limits its

solubility. Absorption can vary from 8-62% & appear to involve an amino acid transporter.

Absorption is affected by food & about 40% of absorbed methyldopa is converted to

methyldopa-O-sulphate by mucosal intestinal cells. Entry into CNS also appears to involve an

active transport process. The ester hydrochloride salt of methyldopa, methyldopate (Aldomet

ester) was developed as a highly water soluble salt that could be used to mask parenteral

preparations. Methyldopate is converted to methyldopa in the body through the action of

esterase.

(D) Imidazoline derivatives, α-agonists

In addition to β-phenylethylamine class of adrenergic receptor agonists, there is a second

chemical class of compounds viz. imidazolines. These imidazolines may be non-selective or may

be selective for either α1 or α2-adrenergic receptors. Structurally, imidazolines for the most part

- 26 -


have the heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via some type

of bridging unit.

SAR of α-agonist imidazoline

Structure-Activity-Relationship of imidazoline α-agonist can be explained by following points:

1. The optimum bridging unit (X) is usually a single amino or methylene group e.g. clonidine

(having amino bridge for α2-activity), oxymetazoline & xylometazoline (having methylene

bridge for α1-activity).

2. Agonistic activity at α1- & α2-receptors is enhanced when aromatic ring is substituted with

halogen atom like chlorine or small alkyl group (lipophilic substitution) like methyl

particurly when they are placed in two ortho positions e.g. clonidine.

3. Bulky lipophilic groups attached to the phenyl ring at meta or para position provide

selectivity for α1-receptors by diminishing affinity for α2-receptors.

2-Arylalkylimidazolines (α1-agonists)

These include naphazoline (Prinine), tetrahydrozoline (Tyzine, Visine), xylometazoline

(Otrivin) & Oxymetazoline (Afrin) are agonists at agonists at α1-adrenoceptors & α2-

adrenoceptors. These agents are topically used for their nasal decongestant & for their

vasoconstrictive effect. They have limited access to CNS, since they essentially exist in an

ionized form at physiological pH, because of very basic nature of imididazoline ring (pKa 9-10).

- 27 -


2-Aminoimidazolines (α2-agonists)

Clonidine: N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine

It is the prototype drug of this class & these are selective α2-agonists. These have some α1-

agonistic activity (vasoconstriction) in periphery. They also act on imidazoline (I1) receptors* in

CNS to control BP (decrease BP). BP may increase at initial due to peripheral α1-agonistic

activity. It crosses blood brain barrier & interact with α2-receptors in CNS (nucleus tractus

solitarius region in brain).

Similar to imidazoline α1-agonist, clonidine has lipophilic ortho-substituents on phenyl ring. The

ortho-chlorine groups afford better activity than ortho-methyl groups at α2-receptors. Presence of

amino group makes the imidazoline ring part of a guanidine group & uncharged form of

clonidine exists as a pair of tautomers. Actually, in case of clonidine, basicity of guanidine group

(pKa 13.6) is decreased to pKa 8.0, because of its direct attachment to the ortho-dichlorophenyl

ring. Thus at the physiological pH, clonidine exist in non-ionized form (20%) required for

passage into CNS.

One of the metabolite of clonidine, 4-hydroxyclonidine is the active α2-agonist but poor

hypotensive. Clonidine mainly acts on α2A-receptors. The positive charge is shared through

resonanmce by all three nitrogen atoms of the guanidine group. Steric crowding by the bulky

ortho-chlorine does not permit a coplanar conformation of two rings.

*Dexmedetomidine & moxonidine are selective I1-agonists used as antihypertensive.

- 28 -


Apraclonidine (Iopidine) & brominidine are selective α2-agonist. They are used to lower

intraocular pressure by reducing aqueous humor production & increasing its outflow.

Apraclonidine is also used to control elevation in intraocular pressure that can occur during the

laser surgery of the eyes. Brimonidine is more active than clonidine. Tizanidine (Zanaflex), by

stimulating α2-receptor, decreases the release of excitatory amino acid neurotransmitter from

spinal cord interneurons. So, it is used in treating spasticity associated with sclerosis or spinal

cord injury.

Guanabenz (Wytensin) & Guanafacine (Tenex) are clonidine derivatives, used as

antihypertensives. Structurally, they can be considered as “open ring imidazolines”. These

compounds have 2,6-dichlorophenyl moiety, found in clonidine, connected with guanidine group

by a two atom bridge. Guanidine group decreases the pKa, due to which, a significant portion of

these drug may exist in non-ionised form at physiological pH. Their machanism of action is same

as that of clonidine.

(E) Dual α- & β-Adrenergic Receptor Agonist

- 29 -


Dobutamine (Dobutrex): It is structurally 1-(methyl)-3-(4-hydroxylphenyl)propyl derivative at

amino group of dopamine. The racemic (±) dobutamine has

direct activity on both α1- & β1-receptors, (+)enantiomer is

potent full agonist at both β1 & β2-receptors. The S(-)

enantiomer exhibit β1-agonistic activity & also a powerful

α1-agonist & vasopressor. Dobutamine is used as a cardiac

stimulant after surgery or CHF. It is metabolized by COMT

& conjugation, but not by MAO.

(F) β-Adrenergic Receptor Agonists

Isoproterenol: 4-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzene-1,2-diol

SAR reveals that due to presence of isopropyl group at N-atom diminishes the α1-activity. It acts

only on β1 & β2-receptors.

It shows cardiac stimulant action by β1-stimulation, while

β2-stimulation leads to bronchodilatation. It is potentially

used in bronchospasm, sometimes it is also used in heart

block. The oral absorption is erratic, duration of action is 1-

3 hours after inhalation. It is metabolized by sulfate & glucuronide conjugation & COMT, but

not by MAO. Due to presence of catechol, it is light sensitive. It is used in asthma & obstructive

pulmonary disease.

Metaproterenol & Terbutaline: These are resorcinol derivatives, so they are β2-agonists, lower

potent than isoproterenol, having loner duration of action due to no action of COMT & MAO.

Metabolism occurs by glucuronide conjugation. These are used in asthma.

Albuterol, Pirbuterol & Salmeterol: due to replacement of m-OH group with hydroxymethyl

moiety, they are β2-agonists. Pirbuterol contains pyridine ring in place of phenyl ring. These re

not metabolized by MAO & COMT but conjugated by sulphate. They are orally active &

- 30 -


duration of action usually ranges from 3-6 hours. Salmeterol is partial agonist at β2-adrenoceptor

& has a potency similar to isoproterenol, longer duration of action (12 hours), due to lipophilic

phenylalkyl substitution on nitrogen atom.

Formeterol & levalbuterol: Formeterol is also

another longer acting β2-agonist, which is associated

with membrane lipid-bilayer for its action. It is used

in asthma in conjunction with an inhaled

corticosteroids.

All the above β2-receptor agonists possess atleast one chiral center & are used as racemic

mixture.

Bitolterol (Tornalate): it is a prodrug of β2-agonist, colterol, N-tert-butyl analog og

norepinephrine. Presence of two p-toluic acid ester provides more lipophilicity than colterol,

makes it orally active. It is administered by inhalation for bronchial spasm & asthma. Bitolterol

has a longer duration of action (5-8 hours). It is metabolized by COMT after hydrolysis & by

conjugation.

Ritodrine (Yutopar): It is also selective β2-agonist, used to control premature labour & to

reverse fetal distress.

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ADRENERGIC ANTAGONISTS

β-Antagonists/β-Sympatholytics/β-Blockers

Basically, for antagonists structural changes should be done in such a way that they contribute to

affinity, but not to intrinsic activity. Structural prerequisite for β-antagonism is

phenethanolamine structure & a hydrophobic group (isopropyl or large) on nitrogen atom. To

eliminate intrinsic activity in a direct gent, the phenolic –OH of NE should be absent.

As in most antagonists, structures are larger than agonists & contain either substituted phenyl

groups, a naphthalene ring or heterocyclic ring system. An example of such compounds is

dichloroisopropterenol (DCI), in which N-isopropylphenethanolamine is retained for affinity,

but the phenolic –OH groups, required for intrinsic activity, have been replaced by Cl atoms.

Unfortunately, DCI was not a full agonist but a partial β-blocker.

Ethanolamines: In case of β-blocker, certain modifications can be made in the basic

isoproterenol structure to yield good β-blocking agent. These modifications include the

followings:

1. Replacement of catechol –OH groups with Cl atoms gives DCI.

2. N,N-disubstituted compounds are inactive.

3. Replacement of catechol-OH groups (electron rich –OH groups) with an electron rich phenyl

group (at 3,4-position) gives pronethalol, which is better β-blocker than DCI.

4. α-Methyl group decreases the activity.

5. Activity is maintained when phenylethyl, hydroxylethyl or methoxyphenylethyl groups are

added to the amine.

6. Cyclic alkyl substitutions on amine are better than corresponding open chain substitutions.

- 32 -


7. Chain length of an amine substituent may extend to a total of 4-carbon atoms without a

terminal phenyl.

8. Addition of an extra acrbon between naphthalene ring & amine decreases activity.

9. Changing from α to β position in naphthalene ring maintains activity.

10. Reduction of one ring to give either of two tetralin analog does not affect the activity.

11. Converting the aromatic portion to phenanthrene or anthracene is disadvantageous. It was

subsequently found that pronethanol derivatives caused lymphoids tumors in the mice. So,

concentration was diverted towards para-substituted ring. The prototype of this class is

methyl sulphonamide compound, sotalol. Meta-substituted rings do not afford good activity,

but substitution of methylsulphamido group with nitro group maintains the activity.

Aryloxypropanolamines: Naphthyloxypropanolamines were found to possess 10-20 times

greater activity than pronethanol & eliminates its carcinogenicity, provided that substitution was

at α-position rather than at β-position of naphthalene ring. Presumably, substution in this position

maintains the same spatial relationship as position maintain in phenylethanolamine series.

Propranolol is prototype drug of this chemical series.

An –OCH2- group is introduced in between aromatic ring &

ethylamine side chain, but nature of aromatic ring & its

substituents are the primary determinant of β-antagonistic activity.

The nature of aryl group also affects the absortion, excretion &

metabolism of β-blocker.

Neither propranolol nor of its alkyl or alkoxy derivatives possess any agonistic activity. β-

Blockers with some agonistic activity are oxprenolol, alprenolol & practolol.

Structure-Activity-Relationship (SAR) of aryloxypropanolamines

- 33 -


1. Most derivatives of this series possesss various substituted phenyl rings rather than naphthyl

ring.

2. Substituton of CH3, Cl, OCH3 or NO2 group on the ring was favoured at position 2 & 3&

atleast at position 4.

3. When dimethyl substitution are made , 3,5-disubstituted compound (metiprolol) was best &

the 2,6 or 2,3,6-substituted compounds were least active. Presumably, this was due to steric

hindrance to rotation about the side chain.

4. Alkenyl or alkenyloxy groups in ortho-positin provided good activity. These compounds can

be considered ring open analog of propranolol. e.g. oxprenolol, alprenolol.

5. To eliminate the lipophilicity (which causes the penetration to blood brain barrier & cardiac

depressant action in addition to β-blocking activity) of propranolol, use of polar methane

sulphonamide was considered. The phenoxypropranolamine side chain was retained, but the

sulphonamide substituent was replaced with an acetamide substituent. This gave rise to new

compound, practolol, (a β1-blocker). In this new series, substitution on either ortho- or meta-

position resulted in loss of both potency & selectivity.

6. Like sympathomimetics, bulky aliphatic groups such as tert-butyl & isopropyl group are

normally found on the amino function. It must be secondary amine for optimal activity.

7. For selective β1-blocker, para- or 4-substitution along with absence of meta-substituents in

the phenoxypropanolamine moiety gives β1-blockers. Practolol (cardioselective antagonist) is

the prototype drug of this series. Exception is metiprolol (non-selective β-blocker).

8. Selective β2-blokers, like β2-agonists, they possess an α-methyl group, but the aromatic

hydroxyl group is generally replaced with other substituents. e. g. H35/25, metalol.

Stereochemistry of β-blockers

The β-blockers exhibit high stereoselectivity in the production of their β-blockling effects. As

with sympathomimetics, the configuration of the hydroxyl bearing carbon of the

aryloxypropanolamine side chain plays a critical role in interaction of β-blockers with β-

receptors. This carbon must possess (S) configuration for the optimal affinity to the β-receptors.

- 34 -


But, mostly β-blockers are used in racemic mixture. Only levobunolol, timolol & penbutolol

with (S) en, the –OH antiomer used. The structural feature of this aromatic portion of the

antagonist, however, appear to perturb the receptor or to interact with it in a manner that inhibit

activation. For phenethanolamines, the –OH group must occupy the same region as in adrenergic

agonists i.e. (R) configuration.

Non-Selective β-blockers

Propranolol (Inderal): It is the prototype drug for β-blockers. It is used for hypertension,

cardiac arrhythmias, angina pectoris, post myocardial infarction etc. It has membrane stabilizing

property (local anesthetic effect or quinidine like effect). Is is well absorbed after oral

administration, but it undergoes extensively first pass metabolism before it reaches the systemic

circulation. Metabolism usually involves N-dealkylation, deamination & oxidation. One

metabolite of particular interest is 4-hydroxypropranolol (a potent β-antagonist & has some

sympathomimetic activity). Main metabolite is naphthoxyacetic acid. Half-life of propranolol

after a single dose is 3-4 hours, which is increased to 4-6 hours after long-term therapy.

- 35 -


Nadolol (Corgard) is used in long-term management of angina pectoris. Timolol (Timoptic,

Blocadren) finds its use in prophylaxis of migraine headache & the therapy following treatment

of myocardial infarction. Satolol is used as an antiarrythymic in treating ventricular arrythmias

& arterial fibrillation, in addition to its β-adrenergic activity. This agent can block the inward K +

current that display cardiac repolarization. Carteolol, timolol, levobunolol & metiprolol are

used topically in open angle glaucoma. These agents lower intraocular pressure with virtually no

effect on pupil size or accommodation. Presumably, they reduce the production of aqueous

humor. Through eye, systemic absortion may occur, producing adverse effects as bradycardia &

acute bronchospasm in patients with bronchospastic diseases. Pindolol possesses modest

membrane stabilizing activity & significant β-agonistic activity. Penbutolol & Carteolol also

have partial agonistic activity, cause less slowing of the resting heart rate than do agents without

this capability. The partial agonistic may be beneficial in patients who are likely to exhibit serve

bradycardia or who have little cardiac reserve.

- 36 -


Timolol, pindolol, penbutolol & carteolol have half-life values in the same range as propranolol.

The half life of nadolol is, however, about 20 hours, making it one of the largest acting β-

blockers. Timolol undergoes first pass metabolism but not to the same extent that propranolol

does. Timolol & penbutolol are metabolized extensively, with little or no unchanged drug

excreted in urine. Pindolol is metabolized by liver to the extent of 60% with the remaining 40%

being excreted in urine unchanged. Nadolol undergoes very little hepatic metabolism.

Selective β1-blockers

β-Blocking agents are very useful in treatment of cardiovascular disease like hypertension etc.

cardioselective β-antagonists are drugs with greater affinity for β1-receptors of heart than for β2-

receptors in other tissues. Such therapeutic agents provide two advantages, first, lack of β2-

antagonistic activity leads to no side effects on bronchioles, so making them safe for users

having bronchitis or asthma. Secondly, absence of vascular β2-receptors mediated vasodilatation

reduces or eliminates the increase in peripheral resistance that sometimes occur after

administration of non-selective β-antagonists.

Atenolol (Tenormin) & metaprolol (Lopressor) are used in treatment of angina pectroris & in

therapy of myocardial infarction. Betaxolol (Kerlone, Betoptic) is only the β1-blocker used in

glaucoma. Acetobutolol (Sectral) & esmolol (Brevibloc) are indicated for treating the cardiac

arrythmias. Esmolol has very short duration of action (t1/2=9 min.) due to rapid hydrolysis of its

ester functionality by esterase present in RBC. The resultant carboxylic acid is an extremely

weak β-antagonist. The acid metabolite has elimination half-life of 3-4 hours & excreted

primarily by kidneys. Acebutolol & betaxolol have weak membrane stabilizing activity. Esmolol

- 37 -


is incompatible with NaHCO3. It must be diluted with an injection solution before

administration.

Acebutolol is converted into diacetolol, which is formed by hydrolytic conversion of amide

group to the amine, followed by acetylation of amines. After oral administration, plasma level of

diacetolol is higher than those of acebutolol. Diacetolol is also a selective β 1-antagonist with

partial agonistic activity. It has little membrane stabilizing activity, half-life of 8-12 hours &

excreted by kidneys.

α-Adrenolytics/α-Blockers/α-Sympatholytics

The chemical classes, which are used as α-blockers are as follow:

1. Non-selective α-blockers

(a) Imidazolines: Tolazoline, Phentolamine

(b) Ergot alkaloids: Ergotamine, Ergotoxine, Dihydroergotamine, Dihydroergotoxine

(c) Miscellaneous: Chlorpromazine, Ketanserin

2. Irreversible (non-equilibrium) α-blockers

(a) β-Haloalkyiamines: Dibenamine, phenoxybenzamine

3. Selective α1-blockers

(a) Quinazolines: Prazosin, Terazosin, Doxazosin

- 38 -


(b) Aryl Sulphonamides: Tamsulosin

(c) Indole alkaoids: Corynanthine, Indoramine


(a) Indole alkaloids: Yohimbine

(b) Tetracyclic compounds: Mirtazapine

Unlike the β-blockers, which bear the clear structural similarities to the adrenergic receptor

agonists like norepinephrine, epinephrine & isoproterenol. The α-adrenergic receptor antagonists

consist of a number of the compounds to diverse chemical structure that bear little resemblance

to α-adrenergic agonists.

1. Non-Selective α-blockers

(a) Imidazolines

Tolazoline (Priscoline) & Phentolamine (Regitine) are imidazoline α-blockers. Both are

reversible blocking (competitive) agents. These are similar to imidazoline α1-agoniss like

naphazoline & xylometazoline but does not have the larger lipophilic substituents required for

agonistic activity i.e. intrinsic activity.

Phentolamine is more effective α-antagonist, but neither drug is useful in treating hypertension.

Both phentolamine & tolazoline are potent, but rather non-specific α-blockers. Both drugs

stimulate gastrointestinal smooth muscles, an action blocked by atropine would indicate

cholinergic activity & they both stimulate gastric secretion, possibly through release of

histamine. Phentolamine is used to prevent or control hypertension episodes that occur in

patients with “pheochromocytoma”. It is also used in combination with papaverine in impotence.

(b) Ergot alkaloids: See hallucinogens, Chapter , Page

2. Irreversible (Non-equilibrium) α-blockers

(a) β-Haloalkylamines*

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Agents in this class when given in adequate doses, produce a slowly developing, prolonged

adrenergic blockade that is overcome by norepinephrine. So these are called as irreversible α-

blockers. Dibenamine is the prototypical agent of this class, but phenoxybenzamine is used

therapectically today.

Mechnism of action of -Haloalkylamine

-Haloalkylamines cause the irreversible blockade of -receptors by alkylation. -

Haloalkylaminesare present in mustard anticancer agents & are highly active alkylating agents.

The initial step involves the formation of an intermediate aziridinium ion (ethylene iminium ion),

which forms an initial reversible complex with receptors. The unshared electrons of the

unprotonated functional group is nucleophilic & displaces the -chlorine atom in an

intramolecular reaction to form highlt reactive, positive charged & electrophilic aziridinium ion.

If this occurs in vicinity of an -receptor, a nucleophilic group (Nu) on the receptor can open the

aziridinium ion in a nucleophilic reaction to form a covalent bond between the receptor & the

drug. The substituents attached to haloalkylamine provide selectivity for binding to -

These are similar to the alkylating agents like the anticancer dug “Cyclophosphamide”.

adrenoceptors, so that the nucleophile is a part of target receptor. The nucleophile (Nu) is

presumably a part of an amino acid side chain, such as cysteine thiol, serine hydroxyl or lysine

amino group. This covalent bond formed is irreversible so long lasting.

- 40 -


Unfortunately, other biomolecules besides the target -receptor are also alkylated. Because of its

receptor non-selectivity & toxicity, the use of phenoxybenzamine is only limited to alleviating

the sympathetic effects of “ pheochromocytoma”. (it is tumor of chromaffin cells of adrenal

medulla producing larger amount of norepinephrine & epinephrine).

Phenoxybenzamine (Dibenzyline): Iit is described as representing chemical sympathectomy

because of its selective blockade of excitatory responses of smooth myocardial muscles. It causes

vasodilatation. It may also block 5-HT receptors. Blockade of Presynaptic 2-receptors may lead

to increased heart rate. The onset of action is slow. Oral phenoxybenzamine is used for pre-

operative management of the patients with “Pheochromocytoma” & in the chronic management

of the patients whose tumors are not amenable to surgery. Only about 20-30% of an oral dose is

absorbed.


(a) Quinazoline Derivatives

Examples are Prazosin (Minipress), terazosin (Hytrin) & doxazosin (Cardura). Structurally, these

agents consist of three components i. e. quionazoline ring, piperazine ring & acyl moiety.

Structure-Activity-Relationships

1. 4- Amino moiety on the quinazoline ring is essential for 1-receptor affinity.

- 41 -


2. Piperazine can be replaced with other heterocyclic moieties (e.g. piperidine) without loss

of activity.

3. The nature of acyl grouphas a significant role in determining pharmacokinetic properties

e.g. when the furan ring (Prazosin) is reduced to tetrahydrofuran ring (Terazosin) , the

compound becomes more hydrophilic, since tetrahydrofuran is more hydrophilic than

furan. In doxazosin, there is a bulky substittion (R) that causes the hindrance in

metabolism causing longer duration of action. (Table 1.6)

Prazosin, Terazosin & Doxazosin: Due to vasodilating action, these agents are used in the

treatment of hyperatension. Prazosin blocks postjunctional 1-receptors without affecting

presynaptic 2-receptors. These agents are also used in the treatment of BPH, where they

improve the flow-rate.

Table 1.6: Pharmacokinetic Profile of 1-adrenergic receptor antagonists

Drug Trade Name Half-Life

(hr)

Duration of

action (hr)

Bioavailability (%)

Prazosin Minipress 2-3 4-6 45-65

Terazosin Hytrin 12 >18 90

Doxazosin Cardura 22 18-36 65

Indoramin Doralese 5 >6 30

Tamsulosin Flomax 14-15 >24 <50% with food,

50-90% fasted

(b) Aryl sulphonamide

Tamsulosin (Flomax) is the representative of this class. It is selective for 1A-adrenergic

receptors, predominantly in prostrate. This is indicated in treatment of BPH (by relaxing trigone

muscles of urinary bladder).

(c) Indoles

Examples of this class are indoramine (Doralese) & corynanthine.

Indoramine (Doralese) : It is an indole derivative, having a piperidine ring in the side chain. It

also blocks H1-receptors & 5-HT receptors in addition to 1-receptors. It has antihypertensive

action.

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(a) Indole alkaloids

Yohimbine & corynanthine are obtained from Pausinysilla yohimbe bark & Rauwolfia roots.

Isomeric indole alkaloids known as yohimbines exhibit different degrees of selectivity, towards

α1 & α2-adrenergic receptors, depending upon their stereochemistry. For example, yohimbine is a

selective antagonist for α2-adrenergic receptors, while corynanthine is selective α2-adrenergic

antagonist. The only difference between these two drugs is the relative stereochemistry of carbon

containing the carbomethyl substituent (C16).

In yohimbine, this group lies in plane of alkaloid ring system, while in corynanthine, it lies in

axial position & thus is out of the plane of the ring system. Yohimbine increases HR & BP as a

result of 2-receptor blockade in CNS. It has been used experimentally to treat male erectile

impotence.

(b) Tetracyclic compounds

Mirtazapine (Rameron) is used toas antidepressant. It also blocks 5-HT2 & 5-HT3 receptors & H1-

receptors.

-Blockers with 1-receptor activity

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Two examples of such compounds are labetalol & carvediol.

(a) Labetalol (Normodyne): It is a phenylethylene derivatives & competitive inhibitor of both

1 & 2 adrenoceptors. Since, it has two asymmetric carbon atoms (1 &1 ’), so it exists in four

isomers. It is used in mixture that is used in the treatment of hypertension. The 1-blocking

solely resides in (1S,1’R) & (1S, 1’S)isomers, previous is more potent. While, β-blocking activity

resides in (1R,1’R) isomer. Labetalol is well absorbed, it exhibits first pass metabolism.

(b) Carvediol (Coreg): Only (S)- enantiomer possesses the β-blocking activity, while both

enantiomer are antagonists of α1-receptor. This drug is also an anti-oxidant & has proliferative

effect on the vascular smooth muscle cells. Thus, it has neuroprotective effect & the ability to

provide major CNS organ protection. It is used in treatment of hypertension & CHF.

Drugs inhibiting metabolism of Catecholamines

Inhibition of enzymes involved in the metabolism of norepinephrine would increase its

concentration at receptors. MAO inhibitors (MAOIs) are useful drugs comes under this category

(see Chapter Antidepressants). MAO oxidizes catecholamines by oxidative-deamination.

Oxidation proceeds through the removal of two amino hydrogens to produce an imine by enzyme

utilizing pyridoxal phosphate (vit. B6) & then by non-enzymatic hydrolysis of the resulting imine

to the aldehyde.

MAOIs can also be used as antihypertensives. This action is not compatible with their

presumable action i.e. increase in the concentration of norepinephrine at Adrenergic receptors.

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This action has been related to alteration in the biosynthesis of norepinephrine caused by

accumulation of intermediates in the biosynthetic pathway & their metabolism of the false

neurotransmitters, which on liberation fail to activate the receptor. Octapamine is an example of

such false neurotransmitter.

Negative feed-back due to accumulation of norepinephrine at the synaptic cleft. As tyrosine

accumulates, it is decarboxylated & hydroxylated to give octapamine.

Synthesis of Adrenergic & Antiadrenergic drugs

Guanethinidine

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Guanedrel

β-Phenylethylamine Derivatives

Terbutaline (Bricanyl, Brethine)

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Salbutamol (Calbuterol, Ventonolin, Provengtil)

Metaraminol

Ritodrine (Yutopar)

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Methoxamine (Vasoxyl)

Ephedrine

Phenylephrine

Naphazoline

Oxymetazoline

Cloniodine

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Guanebenz

Guanefacine

Dobutamine

Propranolol

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Timolol

Nadolol

Pindolol

Acebutolol (N-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}butanamide)

Atenolol

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Betaxolol

Esmolol (Methyl 3-{4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}propanoate)

Metoprolol

Tolazoline

Phentolamine

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Phenoxybenzamine

Prazosin, Terazosin, Doxazosin

Tamsulosin

Mirtazapine

Labetalol

Carvediol

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chapter 1 adrenergic drugs final

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