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In order to use for metabolic studies of tranylcypromine (TCP), TCP-phenyl-d5 was synthesized via the intermediates, 3-benzoylpropionic acid-d5 and trans-2-phenylcyclopropanecarboxylic acid-d5. TCP (0.22mmole/kg) and its deuterated analog were administered s.c. to the rats and GC/MS analyses of the urines led to the detection of N-acetyltranylcypromine (ATCP) and glucuronide conjugate of phenyl-hydroxylated ATCP. MAO activities in rat brain were measured using serotonin as the substrate. In vitro IC50 of ATCP was determined to be 10-3M. The inhibitions by ATCP were not dependent on the preincubation time and were reversed by washing sedimented mitochondrial pellets after the preincubation. In vivo MAO inhibitions at various times of 0.5, 1.5, 3, 6, 12, and 24 hr after the administration of 0.4mmole/kg (i.p.) of ATCP were found to be 0, 13, 73, 90, 89, and 74%, respectively. Similarly, the inhibition percents by 0.015mmole/kg (i.p.) of TCP were 94, 99, 95, 91, 71, and 49%. The results strongly suggest that deacetylated product of ATCP may account for its in vivo MAO inhibition. The relationship between the metabolism via phenylhydroxylation and the in vivo potency of TCP was examined by QSAR study and it was found that groupings discriminating between the compounds with p-substituents and those without them only ensure high correlations, suggesting that ring-hydroxylation which occurs at the para position in most of the compounds is a determining factor to the potency of TCP.
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