A-Methyl-para-tyrosine

NE is synthesized from the amino acid tyrosine, which can be depleted in the brain by administering a competitive inhibitor of its production, a-methyl-para-tyrosine. Tyrosine depletion has been shown to reverse antidepressant responses in individuals treated with antidepressants that inhibit NE reuptake, which suggests a direct role of this neurotransmitter in the course of depression (31). 

The reinforeing properties of psychomotor stimulants have also been linked to the aetivation of eentral dopamine neurons and their postsynaptie reeep-tors. When the synthesis of eatecholamines is inhibited by administering alpha-methyl-para-tyrosine, an attenuation of the subjective effeets of euphoria assoeiated with psyehomotor stimulants oeeurs in man (Jonsson et al. 1971), and a bloekade of the reinforeing effects of methamphetamine occurs in animals (Pickens et al. 1968). Furthermore, low doses of dopamine antagonists will increase response rates for intravenous injections of h-amphetamine (Risner and Jones 1976 Yokel and Wise 1975 Yokel and Wise 1976). 

The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. 

The biosynthetic work on mescaline in the peyote cactus L. williamsii and in the Peruvian cactus T. pachanoi has led to the formulation of biosynthetic pathways according to Scheme 2. A major pathway probably involves decarboxylation of tyrosine followed by hydroxylation to yield dopamine. Dopamine is methylated on the meta hydroxy group to 4-hydroxy-3-methoxyphenethylamine (3-methoxytyramine) which then undergoes hydroxylation to the key intermediate 4,5-dihydroxy-3-methoxyphenethylamine (20). Para-O-methylation of 20 yields 3,4-dimethoxy-5-hydroxyphenethylamine (21), which is the immediate precursor of the main phenolic tetrahydroisoquinolines of peyote. Alternatively, meta-O-methylation yields 3,5-dimethoxy-4-hydroxyphenethylamine (19), which is further efficiently methylated to mescaline. Parallel pathways involving N-methylated compounds probably exist in these cacti (10). 

Some Amaryllidaceae plants possess a group of alkaloids containing a Cg— C2-N-C1-C6 unit. In this unit, the C6-C2-N moiety is derived from tyrosine or tyramine, and the C -Ci part is derived from phenylalanine through cinnamic acid, p-coumaric acid, and protocatechualdehyde [1]. Tyramine (C6-C2-N unit) and protocatechualdehyde (C -Ci unit) are then combined and methylated to form O-methylnorbelladine, which is a common biosynthetic precursor of various Amaryllidaceae alkaloids. Through para,ortho -, ortho,para - and para,paw-phenol coupling of norbel-ladine, the lycorine, galanthamine, and crinine type alkaloids are formed, respectively [2]. 

Oxidative para-para coupling of autumnaline (45) delivers the dienone isoandrocymbine (47), which is O-methylated in the subsequent enzymatic step. This very same para-para coupling reaction has also been biosyn-thetically employed in the route to reticuline (19), key intermediate for the preparation of morphine and other important tyrosine-derived alkaloids (see Section 12.2.3). Next, the tropolone ring is established via the aforementioned skeletal rearrangement. Most likely, this process is achieved by a cytochrome P-450-mediated oxidation with subsequent formation of an intermediary cyclopropane ring... 

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