THE EFFECTS OF A NOVEL AND SELECTIVE INHIBITOR OF TRYPTOPHAN 2,3-DIOXYGENASE ON TRYPTOPHAN AND SEROTONIN METABOLISM IN THE RAT

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl) vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptopha n 2,3-dioxygenase (TDO) (EC 1.13.11.11), were examined on tryptophan c atabolism in vitro and in vivo and on brain levels of tryptophan, sero tonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). 680C91 was a pot ent (K-i = 51 nM) and selective TDO inhibitor with no inhibitory activ ity against indoleamine 2,3-dioxygenase (EC 1.13.11.17), monoamine oxi dase A and B, 5-HT uptake and 5-HT1A,1D,2A and (2C) receptors at a con centration of 10 mu M. 680C91 had no effect on the binding of tryptoph an to serum albumin in plasma and inhibited TDO competitively with res pect to its substrate tryptophan. 680C91 inhibited the catabolism of t ryptophan by rat liver cells and rat liver perfused in situ. The catab olism of L-[ring-2-C-14]-tryptophan and a load dose of tryptophan (100 mg/kg) in vivo were inhibited by prior administration of 680C91. Admi nistration of 680C91 alone produced marked increases in brain tryptoph an, 5-HT and 5-HIAA. A load dose of tryptophan (100 mg/kg), producing increases in brain tryptophan 4-fold greater than that seen with 680C9 1, did not increase brain 5-HT and 5-HIAA to levels greater than those seen with 680C91 and produced a shorter-lasting increase in these par ameters. These data therefore demonstrate the importance of TDO as a r egulator of whole-body tryptophan catabolism and brain levels of trypt ophan and 5-HT and suggest that a greater antidepressant efficacy migh t be achieved with inhibitors of TDO than tryptophan administration al one.