Medicinal chemistry I

Adrenergic drugs
Dr.Lect. Nedhal Abdullah AL.awlq

Textbook: Organic Medicinal & Pharmaceutical Chemistry, Wilson & Gisvold,

12th edition, Chapter 16.

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 List of abbreviations

CAs Catecholamines AD Adrenaline

E Epinephrine
Duration of action DA Dopamine
DOA
CNS Central nervous system ISO Isoproterenol
PNS Peripheral nervous system AchE Acetylcholinesterase
BBB Blood brain barrier
ACh Acetylcholine
SAR Structure activity relationship

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 Adrenergic drugs exert their principal
pharmacological and therapeutic effects by either
enhancing or reducing the activity of the various
components of the sympathetic division of the autonomic
nervous system.
In general, substances that produce effects similar to
stimulation of sympathetic nervous activity are known as
sympathomimetics or adrenergic stimulants.
Those that decrease sympathetic activity are referred
to as sympatholytics, antiadrenergics, or adrenergic-
blocking agents.

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 Adrenergic agents act on adrenergic receptors
(adrenoceptors, ARs) or affect the life cycle of adrenergic
neurotransmitters (NTs), including norepinephrine (NE,
noradrenaline), epinephrine (E, adrenaline), and dopamine
(DA).
These NTs modulate many vital functions, such as the
rate and force of cardiac contraction, constriction, and
dilation of blood vessels and bronchioles, the release of
insulin, and the breakdown of fat .Therefore, adrenergic
drugs constitute abroad class of agents.

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Figure: Motor nerves of the peripheral
nervous system

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 NE,E, and DA are chemically catecholamines
(CAs) ,which refer generally to all organic
compounds that contain a catechol nucleus
(orthodihydroxybenzene) and an ethylamine group.
In a physiological context, the term usually means
DA and its metabolites NE and E.
E contains one secondary amino group and three
hydroxyl groups.

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E and NE each possess a chiral carbon atom; thus, each can
exist as an enantiomeric pair of isomers. The enantiomer with
the configuration (R) is biosynthesized by the body and
possesses the biological activity.
This (R) configuration of many other adrenergic agents also
contributes to their high affinity to the corresponding
adrenoceptors.

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 E is a weak base (pKa 9.9) because of its aliphatic amino
group. It is also a weak acid (pKa 8.7) because of its phenolic
hydroxyl group. It can be predicted that ionized species (the
cation form) of E at physiological pH is predominant ( This
largely accounts for the high water solubility of this
compound as well as other CAs)
Because log P with a value of 0 to 3 is an optimal
window for absorption, we can predict that E has poor
absorption and poor central nervous system (CNS)
penetration (log P of E -0.63).

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Like most phenols, the catechol functional groups in CAs are
highly susceptible to facile oxidation.
E and NE undergo oxidation in the presence of oxygen (air) or
other oxidizing agents to produce a quinone analog, which
undergoes further reactions to give mixtures of colored products,
one of which is adrenochrome.
Hence, solutions of these drugs often are stabilized by the addition
of an antioxidant (reducing agent) such as ascorbic acid or sodium
bisulfite.

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 The first step in CA biosynthesis is the 3-hydroxylation of the
amino acid L-tyrosine to form L- dihydroxyphenyl alanine (L-
DOPA) by tyrosine hydroxylase (TH, tyrosine-3 monooxygenase).
As usual for the first enzyme in a biosynthetic pathway, the
hydroxylation is the rate-limiting step in the biosynthesis of NE.
Further inhibitors of TH markedly reduce endogenous NE and DA
in the brain and NE in the heart, spleen, and other sympathetically
innervated tissues.
This enzyme plays a key role in the regulation of CA biosynthesis
and is, therefore, the logical biological target of some drugs.

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 Some effective TH inhibitors include α-methyl-p-tyrosine,
α-methyl-3-iodotyrosine, and α-methyl-5- hydroxytryptophan.
In general,α-methyl analogs are more potent than the un methylated
analogs. Most of the agents in this category act as competitive
inhibitors of TH. α-Methyl-p-tyrosine (metyrosine), and its methyl
ester have been the TH inhibitors most widely used.

The second step is the decarboxylation of L-DOPA to give DA. The

enzyme involved is DOPA decarboxylase.
The third step is side-chain hydroxylation of DA to give NE.
The last step is the N-methylation of NE to give E in the adrenal
medulla. The reaction is catalysed by the enzyme phenylethanolamine-
N-methyl transferase (PENMT).

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Distribution and Effects of Adrenoceptors and Main Uses of the
Adrenergic Drugs
 A functional classification of the α–receptors was
proposed where α1-receptors were designated as
those that were excitatory, while α2-receptors
purportedly mediated inhibitory responses.
The α1- and α2-receptors each have been divided into
at least three subtypes.
The interaction of adrenergic drugs and the receptors
alters the tertiary or quaternary structure of the
receptor, including the intracellular domain.

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α-receptors are involved in control of the cardio-vascular
system.The α2-receptors not only play a role in the
regulation of NE release (reduce NE release) but also
regulate the release of other NTs, such as acetylcholine and
serotonin.
Both α1 and α2-receptors also play an important role in the
regulation of several metabolic processes, such as insulin
secretion and glycogenolysis.

The α- and β-receptors differ from each other in their

structures, functions, and in the second-messenger system
that is affected.

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 Three β-receptor subtypes have been cloned,
including β1,β2, and β3.
The use of β2-agonists as bronchodilators and β1- or
β1/β2-blockers as antihypertensives is well established.
The β2-receptors are located on smooth muscle
throughout the body, where they are involved in
relaxation of the smooth muscle, producing such
effects as bronchodilation and vasodilatation

The β3-receptor is located on brown adipose tissue

and is involved in the stimulation of lipolysis.
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Drugs Affecting Catecholamine Biosynthesis
Metyrosine (Methyl-L-tyrosine, Demser)
Metyrosine is a much more effective competitive inhibitor of E and
NE production than agents that inhibit any of the other enzymes
involved in CA biosynthesis. Metyrosine differs structurally from
tyrosine only in the presence of an α-methyl group.

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 Sympathomimetic agents produce effects resembling those produced
by stimulation of the sympathetic nervous system. They may be
classified as agents that produce effects by a direct, indirect, or mixed
mechanism of action.
Direct-acting agents elicit a sympathomimetic response by
interacting directly with adrenergic receptors.
Indirect-acting agents produce effects primarily by causing the
release of NE from adrenergic nerve terminals; the NE that is released
by the indirect-acting agent activates the receptors to produce the
response.
Compounds with a mixed mechanism of action interact directly
with adrenergic receptors and indirectly cause the release of NE.

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SAR of adrenergic phenylethylamine agonists

1. Separation of Aromatic Ring and Amino Group.

The greatest adrenergic activity occurs when two carbon atoms
separate the aromatic ring from the amino group. This rule applies
with few exceptions to all types of activities.

2. R1, Substitution on the Amino Nitrogen Determines

α – or β -Receptor Selectivity
Replacing nitrogen with carbon results in a large decline in
activity. The activity is also affected by the number of substituents
on the nitrogen. Primary and secondary amines have good
adrenergic activity, whereas tertiary amines and quaternary
ammonium salts do not.
*As the size of the nitrogen substituent increases, α- receptor
agonist activity generally decreases and β–receptor agonist activity
increases. 37
3. R2, Substitution on the -Carbon (Carbon-2).
Substitution by small alkyl group (e.g., CH3- or C2H5-) slows
metabolism by monoamine oxidase (MAO) but has little overall
effect on DOA of catechols because they remain substrates
for catechol-O-methyl transferase (COMT).

4. OH substitution on the -carbon (carbon-1).

generally decreases CNS activity largely because it
lowers lipid solubility. However, such substitution greatly
enhances agonist activity at both α – and β - receptors.

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 5. Substitution on the Aromatic Ring.
Maximal α- and β- activity also depends on the
presence of 3′ and 4′ OH groups.
Tyramine, which lacks two OH groups, has no affinity for
adrenoceptors, indicating the importance of the OH groups.
Studies of adrenoceptor structure suggest that the OH
groups on serine residues 204 and 207 probably form H
bonds with the catechol OH groups at positions 3 and 4,
respectively.

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 Replacement of the catechol function of ISO with the
resorcinol structure gives a selective β2 agonist ,
metaproterenol.
Furthermore, because the resorcinol ring is not a substrate
for COMT, β -agonists that contain this ring structure tend to
have better absorption characteristics and a longer DOA than
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their catechol-containing counterparts.
Q) Compare between following pair of compounds regarding
DOA

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 In another approach, replacement of the meta-OH of the catechol
structure with a hydroxymethyl group gives agents, such as albuterol,
which show selectivity to the β2-receptor. Because they are not
catechols, these agents are not metabolized by COMT and thus show
improved oral bioavailability and longer DOA.

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 6. CAs without OH Groups.
Phenylethylamines that lack OH groups on the ring and the β-
OH group on the side chain act almost exclusively by causing the
release of NE from sympathetic nerve terminals and thus results
in a loss of direct Sympathomimetic activity.

Because substitution of OH groups on the phenylethylamine

structure makes the resultant compounds less lipophilic,
unsubstituted or alkyl substituted compounds cross the BBB
more readily and have more central activity.

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