Org.
pharmaceutical chemistry 4th stage\ 1st sem
Lec. 3 Adrenergic Agents 2023-2024
Sympathomimetic agents
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 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. As described later, the mechanism by which an agent produces its sympathomimetic
effect is related intimately to its chemical structure
Direct-Acting Sympathomimetic
The structure–activity relationships (SARs)
The parent structure with the features in common for many of the adrenergic drugs is β-
phenylethylamine. The manner in which β-phenylethylamine is substituted on the meta- and
para-positions of the aromatic ring, on the amino (R1), and on α, (R2)-, and β-positions of the
ethylamine side chain influences not only their mechanism of action, the receptor selectivity,
but also their absorption, oral activity, metabolism, degradation, and thus duration of action
(DOA). For the direct-acting sympathomimetic amines, maximal activity is seen in β-
phenylethylamine derivatives containing (a) a catechol and (b) a (1R)-OH group on the
ethylamine portion of the molecule. Such structural features are seen in the prototypical direct-
acting compounds NE, E, and ISO.
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Org. pharmaceutical chemistry 4th stage\ 1st sem
Lec. 3 Adrenergic Agents 2023-2024
Figure: Structure activity relationship of adrenergic phenylethylamine agonists.
Notes
1. A critical factor in the interaction of adrenergic agonists with their receptors is
stereoselectivity. Substitution on either carbon-1 or carbon-2 yields optical isomers.
(1R,2S) isomers seem correct configuration for direct-acting activity.
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.
R1, Substitution on the Amino Nitrogen Determines α- or β-Receptor Selectivity.
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Org. pharmaceutical chemistry 4th stage\ 1st sem
Lec. 3 Adrenergic Agents 2023-2024
1. The amine is normally ionized at physiological pH. This is important for direct agonist
activity, because replacing nitrogen with carbon results in a large decline in activity. The
activity is also affected by the number of substituents on the nitrogen.
2. Primary and secondary amines have good adrenergic activity, whereas tertiary amines
and quaternary ammonium salts do not.
3. The nature of the amino substituent also dramatically affects the receptor selectivity of
the compound. As the size of the nitrogen substituent increases, α-receptor agonist
activity generally decreases and β-receptor agonist activity increases. Thus, NE has more
α -activity than β-activity and E is a potent agonist at α -, β1-, and β2-receptors. ISO,
however, is a potent β1- and β2-agonist but has little affinity for α-receptors.
4. The nature of the substituents can also affect β1- and β2- receptor selectivity. In several
instances, it has been shown that a β2-directing N-tert-butyl group enhances β2-
selectivity. For example, N-tert-butylnorepinephrine (Colterol) is 9 to 10 times more
potent as an agonist at tracheal β2-receptors than at cardiac β1-receptors. These results
indicate that the β-receptor has a larger lipophilic binding pocket adjacent to the amine-
binding aspartic acid residue than do the α-receptors.
5. Increasing the length of the alkyl chain offers no advantage, but if a polar functional
group is placed at the end of the alkyl group, the situation changes. In particular, adding a
phenol group to the end of a C2 alkyl chain results in a dramatic rise in activity, which
can take part in H-bonding.
6. As R1 becomes larger than butyl group, it can provide compounds with α1-blocking
activity (e.g., tamsulosin and labetalol). Large substituents on the amino group also
protect the amino group from undergoing oxidative deamination by MAO.
R2, Substitution on the α-Carbon (Carbon-2)
1. Substitution by small alkyl group (e.g., CH3- or C2H5-) slows metabolism by MAO but
has little overall effect on DOA of catechols because they remain substrates for COMT.
the resistance to MAO activity is more important in noncatechol indirect-acting
phenylethylamines. Because addition of small alkyl group increases the resistance to
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Org. pharmaceutical chemistry 4th stage\ 1st sem
Lec. 3 Adrenergic Agents 2023-2024
metabolism and lipophilicity, such compounds often exhibit enhanced oral effectiveness
and greater CNS activity than their counterparts that do not contain an α-alkyl group. In
addition, compounds with an α-methyl substituent persist in the nerve terminals and are
more likely to release NE from storage sites. For example, metaraminol is an α-agonist
and also exhibits a greater degree of indirect sympathomimetic activity.
2. Methyl or ethyl substitution on the α-carbon of the ethylamine side chain reduces direct
agonist activity at both α- and β-receptors. α-Substitution also significantly affects
receptor selectivity.
In the case of β-receptors, for example, -methyl or ethyl substitution results in
compounds toward the β2-selectivity, whereas in the case of α-receptors, α-
methyl substitution gives compounds toward the α2- selectivity.
Another effect of α-substitution is the introduction of a chiral center, which
has pronounced effects on the stereochemical requirements for activity. For
example, with α-methylnorepinephrine, it is the erythro (1R,2S) isomer that
possesses significant activity at α2-receptors.
OH substitution on theβ-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.
For example, ephedrine is less potent than methamphetamine as a central stimulant, but it
is more powerful in dilating bronchioles and increasing blood. Compounds lacking the β-
OH group (e.g. DA) have a greatly reduced adrenergic receptor activity. Some of the
activity is retained, indicating that the OH group is important but not essential. The R-
enantiomer of NE is more active than the S-enantiomer, indicating that the secondary
alcohol is involved in an H-bonding interaction.
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.
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Org. pharmaceutical chemistry 4th stage\ 1st sem
Lec. 3 Adrenergic Agents 2023-2024
Although the catechol moiety is an important structural feature in terms of yielding
compounds with maximal agonist activity at adrenoceptors, it can be replaced with other
substituted phenyl moieties to provide selective adrenergic agonists. This approach has
been used in particular in the design of selective β2-agonists.
For example, 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 their catechol-containing counterparts.
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.
Modification of the catechol ring can also bring about selectivity at α-receptors as it
appears that the catechol moiety is more important for α2-activity than for α1-activity. For
example, removal of the p-OH group from E gives phenylephrine, which, in contrast to E,
is selective for the α1-receptor. Phenylephrine is less potent than E at both α- and β-
receptors, with β2-activity almost completely absent.
