Medicinal Chemistry

(Jacob Rumans) #1

is therefore the logical point for the inhibition of NE synthesis. DOPA decarboxylase
acts on all aromatic amino acids and requires pyridoxal phosphate (vitamin B 6 ) as a
cofactor. Dopamineβ-hydroxylase, located in the membranes of storage vesicles, is a
copper-containing protein—a mixed-function oxygenase that uses O 2 and ascorbic acid.
Finally,phenylethanolamine N-methyltransferase,located in the adrenal medulla (the
main site of epinephrine synthesis) and in the brain, uses S-adenosyl-methionine as a
methyl donor.


4.3.2.2 Catecholamine Storage


Catecholamine storage utilizes synaptic vesicles of different sizes in different organs.
The largest ones (up to 120 nm) are found in the adrenal medulla (part of the adrenal
glands which are found just above the kidneys in the abdomen) and are called chro-
maffin granules. Catecholamines are stored as their ATP complexes, in a proportion of
4:1, in association with the acidic protein chromogranin. This keeps the neurotransmit-
ter in a hypo-osmotic form even though its concentration is very high (up to 2.5 M) and
also protects it from enzymatic oxidation by monoamine oxidase. The vesicles also
contain the enzyme dopamine β-hydroxylase, proof that NE is synthesized in the vesi-
cle. The vesicles themselves are formed in the cell body and are transported along the
axon to the terminal region.


4.3.2.3 Catecholamine Release


The release of catecholamines has been studied mainly in the adrenal medulla, which
is analogous to the nerve cell. In the medulla, the neuronal impulse releases ACh


NEUROTRANSMITTERS AND THEIR RECEPTORS 219
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