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Basic catecholamine structure and its relationship to their function
The Catechol Ring
The catechol ring is a mere 6-carbon phenyl ring. 3,4-dihydroxybenzene, to
be nerdishly precise. What makes it catechol is the presence of the exciting
hydroxyl groups at the 3 and 4 position. Otherwise, its just boring old phenol.
6
5
HO
1
These two hydroxyl groups are what enables the catechol ring to be effective
at the beta and alpha catecholamine receptors.
2
4
3
HO
Yes, there is an actual chemical called catechol, and according to Wikipedia about 20 million tons of it are produced annually, as a precursor to pesticides flavours and fragrances. Its
rapidly soluble in water. The factories manufacture it by reacting phenol with hydrogen peroxide. Phenol is essentially the same benzene ring but with only one hydroxyl group; it
originates from benzene when benzene reacts with nitrous oxide. Catechol is called catechol because it was first derived from the juice of Mimosa catechu. In case you needed to know .
β- Phenylethylamine, he who begat all catecholamines and their ilk
Phenyl
Ethylamine
CH2
CH2
NH2
Mighty phenylethylamine is the grandfather of all these
sympathomimetic drugs, ranging from inotropes to
antidepressants bronchodilators and party pills.
This basic backbone is what its all about.
The absence of hydroxyl groups permits phenylethylamine
to penetrate the blood brain barrier.
The contribution of each individual structural element to the function of the molecule
The depicted molecule is dopamine, the stereotyped catecholamine
Beta- carbon atom
Hanging an extra hydroxyl group here tends to decrease lipid solubility, and thus decrease CNS penetration
ANY additional group here GREATLY increases alpha and beta receptor agonist activity.
Alpha- carbon atom
Any additional groups here block the action of MAO, and thus increase the half life.
Drugs with this structure dwell longer at the synapse, and act as indirect sympathomimetics
6
5
HO
1
2
4
3
HO
β
α
CH2
CH2
NH2
Amine Group
Amine group
A methyl group here confers alpha selectivity.
The smaller the group, the more alpha effect there is.
Increase of the alkyl substituent on the amine group increases
the molecules preference for beta receptors instead of alpha
The bigger the alkyl substituent, the more beta effect there is.
The Aromatic Ring and Catechol hydroxyl groups
It all depends where you substitute the extra groups.
You need two to have the maximum receptor affinity.
However, having two polar hydroxyl groups decreases lipid solubility and keeps you out of the
brain. Having no groups like phenylethylamine results in good CNS penetration.
Positions 3 and 5 = beta-2 selectivity in compounds with large amino substituents.
From Peck and Hill “Pharmacology for Anaesthesia and Intensive care” as well as the mighty “Handbook of Pharmacology and Physiology in Anaesthetic Practice” by Stoelting and Hillier. A