Monoamine-synthesis inhibitor

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Grahame-Smith, DG (1971) Studies in vivo on the relationship between brain tryptophan, brain 5HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J. Neurochem. 18 1053-1066. 

Recently research has focused on the action of lithium on serotonergic function. Lithium has been shown to facilitate the uptake and synthesis of 5-HT, to enhance its release and to increase the transport of tryptophan into the nerve terminal, an effect which probably contributes to the increased 5-HT synthesis. The net effect of these changes is to produce postsynaptic receptor events, which might explain why lithium, in combination with tryptophan and a monoamine oxidase inhibitor or a 5-HT uptake inhibitor, is often effective in therapy-resistant depression. 

Asymmetric allylic C-H activation of cydohexadiene systems has been used for the asymmetric synthesis of several compounds of pharmaceutical relevance. The key step in the asymmetric syntheses of the monoamine reuptake inhibitor (-i-)-indatrahne 185 was the C-H insertion reaction of the aryldiazoacetate 183 with 1,4-cyclohexadiene (Scheme 14.24). The product 184, obtained in 83% yield with 93% enantiomeric excess, is readily converted to (-i-)-indatraline using standard synthetic procedures [132]. 

Synthesis and Biochemical Evaluation of Fiuorinated Monoamine Oxidase Inhibitors... 

Devise a synthesis for the monoamine oxidase inhibitor tranylcypromine (rac-A). 

The monoamine oxidase inhibitors epitomize cyclical fashions in drug use and the impact of adverse effects. They were the first psychotropic drugs for which a clear biochemical action was defined. Early excitement was quickly tempered by reports of liver toxicity with the hydrazine derivatives, leading to synthesis of the cyclopropylamine drug, tranylcypromine, which in turn elicited the food and drug interactions that led to an overall decline in popularity. 

Practical applications include the synthesis of rran5-2-phenylcyclopropanamine (trade name tranylcypromine), an antidepressant acting as a monoamine oxidase inhibitor [20 a], of 2,2-dimethylcyclopropane carboxylate from isobutene [20 b], a key step in the commercial production of cilastatin, 3 (eq. (4)), and of esters of chrysanthemic acid 4 (using the methylene bis(diphenyloxazoline) 5) [ 17, 21 ] (eq. (5)). Cilastatin is a dehydropeptidase which acts as an in vivo stabilizer of the car-bapenem antibiotic imipenem with achiral diazoesters. 

The Pd-catalyzed amidation shown is used to synthesize Lazabemide, a monoamine oxidase inhibitor, in 65% yield.127 This transformation replaced an eight-step synthesis route to the same drug. Propose a catalytic cycle for this aminocarbonylation by assuming that the first step is OA of the pyridyl chloride. 

Amphetamine [XXII) is a central stimulant and many would not classify it with the antidepressant drugs proper. It has, however, been extensively used in the treatment of depression, it produces euphoria and some at least of its actions may be due to inhibition of monoamine oxidase. However, it also inhibits dopamine- S-oxidase, impairs the noradrenaline binding capacity of the brain and has direct sympathomimetic activity. Its classification with the antidepressants seems, therefore, to be justified, but it is not included with the monoamine oxidase inhibitors, since only a small part of its action can be attributed to enzyme inhibition. Amphetamine is a potentially addictive drug and it should be used cautiously and over short periods of time. Other compounds which are used, if at all, only for the treatment of mild depression, include methylphenidate [XXIII), pipradol [Table 5.2) and deanol (XXIV). The last named compound is interesting since it may owe its effectiveness to a stimulant action on acetylcholine synthesis > . ... 

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