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 tryptophan 2,3-dioxygenase (TDO) (EC 1.13.11.11), were examined on tryptophan catabolism in vitro and in vivo and on brain levels of tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). 680C91 was a potent (Ki = 51 nM) and selective TDO inhibitor with no inhibitory activity against indoleamine 2,3-dioxygenase (EC 1.13.11.17), monoamine oxidase A and B, 5-HT uptake and 5-HT1A,1D,2A and 2C receptors at a concentration of 10 microM. 680C91 had no effect on the binding of tryptophan to serum albumin in plasma and inhibited TDO competitively with respect to its substrate tryptophan. 680C91 inhibited the catabolism of tryptophan by rat liver cells and rat liver perfused in situ. The catabolism of L-[ring-2-14C]-tryptophan and a load dose of tryptophan (100 mg/kg) in vivo were inhibited by prior administration of 680C91. Administration of 680C91 alone produced marked increases in brain tryptophan, 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 680C91, 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 parameters. These data therefore demonstrate the importance of TDO as a regulator of whole-body tryptophan catabolism and brain levels of tryptophan and 5-HT and suggest that a greater antidepressant efficacy might be achieved with inhibitors of TDO than tryptophan administration alone.
Salter
M
M
Wellcome Research Laboratories, Beckenham, Kent, UK.
Hazelwood
R
R
Pogson
C I
CI
Iyer
R
R
Madge
D J
DJ
D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002474:Cell-Free System; D004305:Dose-Response Relationship, Drug; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors*
D000928:Antidepressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; C093792:TDO inhibitor LM10; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D014366:Tryptophan Oxygenase