KOPIN 277nephrine was a deaminated and O-methylated product, vanillylmandelic
acid (VMA).^3 They had assumed that deamination occurred first and
O-methylation followed. As indicated above, Axelrod found that
O-methylation of the catecholamines could occur first and that this was
the more important pathway for metabolism of administered catechol
amines.^4 VMA could be formed by deamination of the metanephrines.
Axelrod’s demonstration of O-methylation of epinephrine and discov
ery of the enzyme, catechol-O-methyl transferase, was possible because
he could obtain S-adenosylmethionine, required for all methylation reac
tions, from Giulio Cantoni’s Laboratory of Cellular Pharmacology, which
was just down the hall.
At the symposium, von Euler, who was awarded a Nobel Prize in 1970,
described the method that was then being used in his laboratory for
catecholamines. This method was based on the formation of a fluorescent
trihydroxyindole formed by oxidizing catecholamines and became the
most widely used method for many studies during the next decade.
Robert Furchgott, who was awarded the Nobel Prize in 1998 for his
discovery of nitric oxide as a signaling molecule, talked about the adre
nergic receptors, how the drugs act at these receptors. Earl Sutherland
presented for the first time his discovery of adenosine-3’,5’-phosphoric
acid (cyclic AMP), which was formed from ATP in the presence of epi
nephrine. The discovery of this crucial “second messenger” in the actions
of hormones and neurotransmitters was the reason that he won the
Nobel Prize in 1971.
In his presentation, George Koelle, who was one of the organizers of
the symposium and was professor of pharmacology and physiology at the
University of Pennsylvania, emphasized the importance of understand
ing how the actions of catecholamines were terminated by mechanisms
that do not involve metabolic transformation. He listed five different
mechanisms, which Thomas Butler had discussed, as the means of ter
minating the actions of norepinephrine. None of them were correct.
Axelrod found the right answer, which was one of the discoveries that
led to his Nobel Prize awarded in 1970.^5 As discussed above, Axelrod’s
first discoveries were in relation to the importance of O-methylation,
and the major route of metabolism of administered epinephrine or
norepinephrine. When injected into the bloodstream, O-methylation is