Tranylcypromine, synthesis

Hammond postulate and, 197-199 Translation (RNA), 1109-1111 Tranylcypromine, synthesis of, 935 Tree diagram (NMR), 466 Triacylglycerol, 1061... 

With the exception of tranylcypromine (a phenylcycloalkylamine), the first MAOIs (e.g. iproniazid, isoniazid, phenelzine, isocarboxazid) were derivatives of hydrazine (originally used as a rocket fuel) (Fig. 20.2). All are irreversible inhibitors of the enzyme and restoration of MAO activity requires the synthesis of new enzyme. 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

Several compounds affecting various 5-HT functional parameters (uptake inhibition (fluoxetine), metabolism (tranylcypromine) or synthesis (5-OH tryptophan, 5-HTP)) had no effect on subemetic doses of cisplatin [110]. In fact, tranylcypromine and 5-HTP antagonized emesis of cisplatin. Thus these results would favour an inhibitory role of 5-HT instead of emetogenic. It is conceivable that an excess of 5-HT may desensitize 5-HT3 receptors that may result in a reduced sensitivity to emetogenic stimuli. 

Iproniazic was the first widely prescribed MAOI. Realization that this drug can produce rare but dangerous liver toxicity led to the synthesis of the other hydrazine MAOIs, such as isocarboxazid, nialamide, and phenelzine, as well as the nonhydrazine MAOIs, tranylcypromine, and pargyline. 

Csuk R, Schabel MJ et al (1996) Synthesis of the enantiomer of the antidepressant tranylcypromine. Tetrahedron Asymmetry 7 3505-3512... 

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

Tranylcypromine contains a cyclopropane ring and construction of this unit must be the overriding consideration in planning a synthesis for the compound. On the basis of the constitution given for the compound a ring closure reaction appears to be rather impracticable. Consequently, cycloaddition reactions must be considered for which three possibilities exist as shown by the disconnections a, b, or c in the formula below. 

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 first-generation MAO inhibitors phenelzine (19)and tranylcypromine (23) act as substrates for MAOA and MAOB but are converted by the enzyme to highly reactive intermediates that then react irreversibly with the enzyme to cause an irreversible inhibition. of activity. Recovery of MAO activity after exposure to these MAO inhibitors requires the synthesis of new enzyme protein, a process that takes some weeks to completely restore activity (173, 174). A clinical antidepressant response is associated with an inhibition of platelet MAO activity of approximately 80%, and measurement of platelet MAO activity can be used to monitor treatment dose regimes (175). 

Tranylcypromine, a monoamine oxidase inhibitor also inhibits prostacyclin synthetase in vitro (IC50 = 160 jig/m ) [96]. This is much weaker than the inhibition induced by the fatty acid hydroperoxides (IC50 = 0.5 /xg/ml) [85]. Fortunately, the latter products are not active when administered in vivo due to active peroxidases which reduce the hydroperoxides to the inactive hydroxides. Other inhibitors of prostacyclin synthesis are the endoperoxide analogs (9,11-diaza and 9,11-epoxyimino-prosta-5,13-dienoic acid) [97] and an indole hydroperoxide [98]. 

Another technique O for measuring turnover time of 5-HT makes use of a blockade of monoamine oxidase with a number of inhibitors (including pargyline and tranylcypromine) and calculation of the rate of synthesis from the product of the rate constant of 5-hydroxyindole acetic acid (5-HlAA) decline and the normal 5-HIAA level. On the other hand, because of variation seen in the rate of Increase in NE after inhibition of MAO in different species, it has been inferred that the rate of increase in NE after blockade of MAO is not a good measure of rate of synthesis of this... 

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