Structure and function relationships of catecholamine molecules

This chapter is relevant to Section M (i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to "describe the autonomic nervous system, including anatomy, receptors, subtypes and transmitters (including their synthesis, release and fate)". Somewhere in there, presumably on the edges of the parenthesis between "transmitters" and "including", is the discussion of the catecholamine molecule, and the implications of its shape for the way it is received as a ligand and metabolised. This is a well-worn path for anaesthesia trainees whose cruel training program apparently still insists on the ability to draw molecules, but does not appear to be essential for the CICM exam candidate, who merely needs to draw CRRT circuit diagrams instead.

In terms of articles, it would appear that one can either have a lucid explanation, or a detailed one, but not both. If one were to draw a continuum connecting those properties, the 50-page dossier by Giescke & Hebert (1979) would definitely belong at one end, Aaron (1990) and that chapter of Katzung at the other,  and Nichols & Ruffolo (1991) somewhere near the middle. Before engaging with these excellent resources, the time-poor reader is reminded that the examinability of this topic is basically zero.

The Catechol Ring

catechol molecule

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. 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, who begot all sympathomimetics

phenylethylamine molecule

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, though what it does there, no one knows. Alexander Shulgin, whose foundational work on phenylethylamines has informed psychedelic laboratory science for the last sixty years, of phenylethylamine, with sadness said:

"Here is the chemical that is central to this entire book.  This is the structural point of departure for every compound that is discussed here. It is the RPS in PIHKAL. It is without activity in man! Certainly not for the lack of trying, as some of the  dosage trials that are tucked away in the literature (as abstracted in the "Qualitative Comments"  given above) are pretty heavy duty. Actually, I truly doubt that all of the experimenters used exactly that phrase, "No effects," but it is patently obvious that no effects were found. It happened to be the phrase I had used in my own notes."

In short, it does nothing interesting. However it is an important skeleton from which one can hang interesting organic groups, to make changes to its activity. 

Structure and function relationship of catecholamines

structure and function relationship of catecholamines

  • 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
  • Amine group
    • The smaller this tail group, the more alpha effect there is.  For example, noradrenaline has nothing here, and is a potent alpha-selective agonist. Add a short methyl group, and you get adrenaline, which has a potent nonselective beta effect. Make it longer, and you get something like salbutamol. In short, increasing the alkyl substituent on the amine group increases the molecules preference for beta receptors instead of alpha, and 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 confer a beta-2 selectivity in compounds with large amino substituents.

References

Giesecke, Johan, and Hans Hebert. "The molecular structure of adrenergic and dopaminergic substances." Quarterly Reviews of Biophysics 12.3 (1979): 263-313.

Aaron, Cynthia K. "Sympathomimetics." Emergency medicine clinics of North America 8.3 (1990): 513-526.

Nichols, Andrew J., and Robert R. Ruffolo. "Structure-activity relationships for α-adrenoceptor agonists and antagonists." Alpha-Adrenoceptors: Molecular Biology, Biochemistry and Pharmacology. Vol. 8. Karger Publishers, 1991. 75-114.

Carlström, D., and R. Bergin. "The structure of the catecholamines. I. The crystal structure of noradrenaline hydrochloride." Acta Crystallographica 23.2 (1967): 313-319.

Pratesi, P. "Chemical structure and biological activity of catecholamines." Pure and Applied Chemistry 6.3 (1963): 435-450.