Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase.

The synthesis of (o-nitrobenzoyl)-, (m-nitrobenzoyl)-, and (p-nitrobenzoyl)alanine (o-, m-, and p-NBA), three new kynurenine analogues, and their evaluation as inhibitors of kynureninase and kynurenine-3-hydroxylase are reported. The most potent of these compounds, m-NBA, has an IC50 of 0.9 +/- 0.1 microM as an inhibitor of kynurenine-3-hydroxylase and of 100 +/- 12 microM as an inhibitor of kynureninase. When administered to rats, m-NBA significantly increases the concentration of kynurenine and kynurenic acid in the brain as well as in blood and in the liver. m-NBA has also been shown to increase the concentration of kynurenic acid in hippocampal extracellular fluid. This increase is associated with sedative and anticonvulsant activities, thus confirming the possibility of antagonizing L-glutamate-mediated effects by modulating the kynurenine pathway of L-tryptophan metabolism.

Effect of intraduodenal administration of 23-methyl-UDCA diastereoisomers on bile flow in hamsters.

3 alpha,7 beta-Dihydroxy-23-methyl-5 beta-cholan-24-oic acid (MUDCA) and its two diastereoisomers, alpha- and beta-MUDCA, were infused intraduodenally in biliary fistula hamsters in order to evaluate the effect on bile flow and their hepatic biotransformation processes compared with the natural analog ursodeoxycholic acid (UDCA). In addition, the corresponding glycine conjugates were compared. The bile acids were administered at different doses (0.7-6 mumol/min/kg) over periods of 90 min. The results indicate that the racemic mixture exhibits a potent choleretic effect at both low and high doses, while the two individual diastereoisomers show this effect only at high doses. The presence of a C-23 methyl group in the side chain prevents hepatic amidation and alternative conjugations occur, such as glucuronidation, in order to facilitate their biliary secretion. Biotransformation of the methyl derivatives of UDCA occurred mainly by conversion to more polar glucuronide conjugates. There was little alteration to the molecule and, unlike UDCA, very little amidation occurred. These data indicate that the presence of a C-23 methyl group prevents the usual side-chain amidation common to the most naturally occurring bile acids and that glucuronidation is a requisite for efficient biliary excretion.

Synthesis, absolute configuration and activity at N-methyl-D-aspartic acid (NMDA) receptor of the four D-2-amino-4,5-methano-adipate diastereoisomers.

The four D-2-amino-4,5-methano-adipates 26, 27, 32, 33 were synthesized and their biological activity at the N-methyl-D-aspartate (NMDA) receptor was assessed. The synthesis involved as a key step a rhodium acetate dimer catalyzed addition of ethyl diazoacetate to the protected D-allylglycine (17). In vitro receptor binding using L-[3H]glutamate as the radioligand provided affinity data, while modulation of [3H]TCP binding was used as a functional assay. The analogues were also evaluated in [3H]kainate and [3H]AMPA binding to assess selectivity over non-NMDA glutamate receptors. Three of the four diastereoisomer, D-CAA B (27), C (32) and D (33) were shown to have agonist properties at the NMDA-site, while the fourth, (2R,4R,5R) D-CAA A (26) was characterized as an NMDA-site atypic antagonist.