Catecholamines biological actions

Another example is levodopa, a promising drug for Parkinson s disease. It was made possible because of our considerable knowledge of the metabolism and biological action of levodopa and catecholamines in general. Parkinsonism patients have lowered levels of dopamine in specific areas of the brain. But since dopamine does not penetrate into the brain to any appreciable extent, it was necessary to administer its precursor, levodopa, to correct the deficiency. Subsequently, Cotzias (2) contributed to the successful treatment of Parkinsonism by showing that large doses of levodopa were most effective. 

The mammalian carotid body expresses a variety of neurochemicals and their receptors (see Tables 1 and 2). The transmitters expressed in the carotid body can be classified into two major categories conventional and imconventional. The conventional class of neurotransmitters includes those that are stored in vesicles and exert their effect via activation of specific receptors. Examples of this class include catecholamines, acetylcholine, and neuropeptides, whereas gas molecules like nitric oxide (NO) and carbon monoxide (CO) form the class of unconventional neurotransmitters. These molecules are generated spontaneously by way of enzymatic reactions and mediate their biological actions by either activation... 

Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

The pioneer work on the connexion between constitution and activity in the phenylethylamine series of sympathomimetic drugs was carried out by Barger and Dale (1910). It has since become clear that direct action of the hormone and neurotransmitter type, is strongest in examples with hydroxy-groups in the 3-and 4-positions of the benzene ring, i.e. the catecholamines such as norepinephrine, epinephrine and dopamine. The indirect action of examples without these embellishments has been outlined in Sections 9.4.3 (p. 358) and 7.6.3 (p. 300). As recounted in Section 12.1 the D-catecholamines (Fig. 12.1) have much more biological activity than their L-enantiomers. 

Minor metabolites that accumulate because of the alternate pathways utilized in phenylketonuria may normally serve either physiological or pharmacological roles in the nervous system. To aggravate the deficiency of tyrosine created by shunting into these minor pathways in PKU, phenylalanine inhibits tyrosine transport across biological membranes. In turn, this curtails the source of neuroactive tyrosine derivatives that can be synthesized, including tyramine, octopamine, and the catecholamines. One can speculate that such deficiencies could interfere with neurotransmitter action. 

The biochemical and histochemical data for Lu 5-003 (22) and nine of its analogs show that these compounds have a selective action on the membrane pump mechanism of the central and peripheral catecholamine neurons and have little or no anticholinergic activity.26 The synthesis and biological activity of 23. a "bridged" amitriptyline, and of several related structures have been reported. These tetracyclic structures did not show significant activity in reversing reserpine-induced hypothermia in mice.27... 

Pargyline is a potent irreversible inhibitor of a flavin-linked monoamine oxidase (MAO) and has found clinical application. The latter catalyzes the inactivation of biologically important catecholamines. It forms a covalent bond with the enzyme via the flavin cofactor and the mode of action is believed to be as shown in Scheme 7.1. 

The naturally occurring catecholamines—dopamine (DA) (1), / -norepinephrine (/ -NE) (2), and / -epinephrine (/J-EPI) (3)— have many imiK)rtant biological functions. These catecholamines are produced in vivo from L-tyrosine. Tyrosine is first converted to dihydroxyphenylalanine (DOPA) by aromatic hydroxylation. L-DOPA is then decarboxylated to give DA, which is subsequently converted to / -NE by p-hydroxylation. DA is a vital neurotransmitter in the central nervous system (CNS) and has actions on the kidneys and heart. Norepinephrine is also present as a neurotransmitter in the CNS, and is the principal neurotransmitter of the peripheral sympathetic nervous system. Epinephrine, which is elaborated from / -NE by N-methylation in the adrenal medulla, has potent actions on the heart, smooth muscle, and other organs (/). 

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