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Structure Activity Relationships

This document discusses the structure-activity relationships of direct-acting sympathomimetic amines. It explains that compounds with a catechol group and (1R)-OH group have maximal activity. Receptor selectivity is determined by substitutions on the amino nitrogen. Compounds can be selective for alpha-1, alpha-2, beta-1, beta-2 or beta-3 receptors depending on these substitutions. Indirect-acting compounds release endogenous norepinephrine while direct-acting compounds act on adrenergic receptors themselves.

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366 views

Structure Activity Relationships

This document discusses the structure-activity relationships of direct-acting sympathomimetic amines. It explains that compounds with a catechol group and (1R)-OH group have maximal activity. Receptor selectivity is determined by substitutions on the amino nitrogen. Compounds can be selective for alpha-1, alpha-2, beta-1, beta-2 or beta-3 receptors depending on these substitutions. Indirect-acting compounds release endogenous norepinephrine while direct-acting compounds act on adrenergic receptors themselves.

Uploaded by

Mompati Letsweletse
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Direct-Acting Sympathomimetics

STRUCTURE–ACTIVITY RELATIONSHIPS
The parent structure of many adrenergic drugs is β-phenylethylamine.

The modifications of β-phenylethylamine influence not only the mechanism


of action, the receptor selectivity, but also their absorption, oral activity,
metabolism, 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.

Optical Isomerism

For CAs, the more potent enantiomer has the (1R) configuration.

Separation of Aromatic Ring and Amino Group


The greatest adrenergic activity occurs when two carbon atoms separate the
aromatic ring from the amino group.

R1, Substitution on the Amino Nitrogen Determines α- or β-Receptor


Selectivity

Primary and secondary amines have good adrenergic activity, whereas


tertiary amines and quaternary ammonium salts do not.

1
The nature of the amino substituent also 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.

N-tert-butyl group enhances β2-selectivity.

R2, Substitution on the α-Carbon (Carbon-2).


Substitution by small alkyl group (e.g., CH3- or C2H5-) slows metabolism by
MAO. This is very important for non-catechol compounds where the
addition of small alkyl group increases the resistance to metabolism and
lipophilicity, so such compounds often exhibit enhanced oral effectiveness
and greater CNS activity than other compounds that do not contain an α-
alkyl group.

OH substitution on the β-carbon (carbon-1)

1- Greatly enhances agonist activity at both α- and β-receptors.


2- Largely decreases CNS activity because it lowers lipid solubility.

Substitution on the Aromatic Ring

Maximal α- and β-activity also depends on the presence of 3´ and 4´ OH


groups.

2
Compounds without one or both phenolic OH substituents are not
metabolized by COMT, and they are orally active and have longer duration
of action.

Although the catechol moiety is important maximal agonist activity at


adrenoceptors, it can be replaced with other substituted phenyl moieties to
provide selective adrenergic agonists.

CAs without OH Groups

The loss of OH groups on the ring and the β-OH group on the side chain
lead to compounds that:

1- Act almost by causing the release of NE from sympathetic nerve terminals


(loss of direct sympathomimetic activity).
2- - Have more central activity (more lipophilic compounds).

Imidazolines and α-Adrenergic Agonists

A second chemical class of α-agonists is the imidazolines. These


imidazolines can be nonselective, or they can be selective for either α1- or
α2-receptors. Structurally, most imidazolines have their heterocyclic
imidazoline nucleus linked to a substituted aromatic moiety via some type of
bridging unit. The optimum bridging unit (X) is usually a single methylene
group or amino group.

ENDOGENOUS CATECHOLAMINES

The three naturally occurring catecholamines DA, NE, and E are used as
therapeutic agents.

3
α-ADRENERGIC RECEPTOR AGONISTS

All selective α1-agonists have therapeutic activity as vasoconstrictors.


Structurally, they include (a) phenylethanolamines such as phenylephrine,
metaraminol, and methoxamine and (b) 2-arylimidazolines such as
xylometazoline, oxymetazoline, tetrahydrozoline, and naphazoline.

Phenylephrine

It differs from E only in lacking a p-OH group. It is orally active, and its
duration of action (DOA) is about twice that of E because it lacks the
catechol moiety and thus is not metabolized by COMT.

It is used for hypotension and as a nasal decongestant in both oral and


topical preparations.

Naphazoline, tetrahydrozoline, xylometazoline, and oxymetazoline

They are 2-aralkylimidazolines α1-agonists. These agents are used for their
vasoconstrictive effects as nasal and ophthalmic decongestants. They have
limited access to the CNS, because they essentially exist in an ionized form
at physiological pH caused by the very basic nature of the imidazoline ring.

4
Clonidine

It differs from 2-arylimidazoline α1-agonists mainly by the presence of o-


chlorine groups and a NH bridge. Clonidine has antihypertensive activity
due to its ability to interact with α2-receptor in the brain which cause a
decrease in sympathetic out flow CNS.

The ability of clonidine to exert an antihypertensive effect depends on the


ability of these compounds to enter the CNS and interact with the α2-
receptor in the brain. For clonidine, the basicity of the guanidine group
(typically pKa = 13.6) is decreased to 8.0 because of the inductive and
resonance effects of the dichlorophenyl ring. Thus, at physiological pH,
clonidine will exist to a significant extent in the nonionized form required
for passage into the CNS.

Methyldopa (L-α-methyldopa)

It differs structurally from L-DOPA only in the presence of a α-methyl


group. Methyldopa is transported actively into CNS, where it is
decarboxylated by AADC in the brain to (1R, 2S)-α-methyldopamine. This
intermediate, in turn, is stereospecifically β-hydroxylated by DBH to give
the (1R, 2S)- α -methylnorepinephrine. This active metabolite is a selective
α2-agonist. It is currently postulated that α -methylnorepinephrine acts on α2-
receptors in the CNS in the same manner as clonidine, to decrease
sympathetic outflow and lower blood pressure.

5
DUAL α- AND β-AGONISTS/ANTAGONISTS

Dobutamine

It possesses a center of asymmetry, and used clinically as racemic mixture.


The (-) isomer of dobutamine is a potent α1-agonist. In contrast, (+)-
dobutamine is a potent α1-antagonist, which can block the effects of (-)-
dobutamine. Importantly, the effects of these two isomers are mediated via
β1-receptors. Both isomers appear to be full agonists. It is a positive
inotropic agent administered intravenously for congestive heart failure.

Dobutamine contains a catechol group and is orally inactive and thus is


given by intravenous infusion.

6
β-ADRENERGIC RECEPTOR AGONISTS

Isoproterenol

Because of an isopropyl substitution on the nitrogen atom, it has virtually no


α-activity. However, it does act on both β1- and β2-receptors.

The cardiac stimulation caused by its β1-activity and its lack of oral activity
(why?) have led to its diminished use and favoring the more selective β –
agonists.

β2-Adrenergic Receptor Agonists

Albuterol, pirbuterol, salmeterol and Formoterol

They are selective β2 mainly used as bronchodilator. They are not


metabolized by either COMT or MAO. They are thus exhibit a longer
duration of action than isoproterenol.

7
β3-Adrenergic Receptor Agonists.

Activation of the β3-receptor is thought to be a possible approach for the


treatment of obesity, type 2 diabetes mellitus, and frequent urination.
Therefore, it is an attractive target for drug discovery. Selective β 3-agonists
have been developed, but they have not been approved for therapeutic use.

Indirect-Acting Sympathomimetics

Indirect-acting sympathomimetics act by releasing endogenous NE. They


enter the nerve ending by way of the active-uptake process and displace NE
from its storage granules.

L-(+)-Pseudoephedrine

It is a naturally occurring alkaloid. This agent is found in many OTC nasal


decongestant and cold medications.

Whereas ephedrine has a mixed mechanism of action, L-(+)-


pseudoephedrine acts mostly by an indirect mechanism and has virtually no
direct activity. The structural basis for this difference in mechanism is the
stereochemistry of the carbon atom possessing the β-OH group.

8
Sympathomimetics with a Mixed Mechanism of Action

They have no hydroxyls on the aromatic ring but do have a β-hydroxyl


group.

D-(-)-Ephedrine

This drug is an alkaloid. It is not metabolized by either MAO or COMT and


therefore has more oral activity and longer duration of action than E.
Ephedrine has two asymmetric carbon atoms so it has four isomers.

D (-) isomer is the most active of the four isomers as a pressor amine
because has the correct (1R,2S) configuration for optimal direct action at
adrenergic receptors.

Lacking phenolic OH groups, ephedrine is less polar and, thus, crosses the
BBB far better than do other CAs.

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