1.The effects of an inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake in the rat.
Salter M;Hazelwood R;Pogson CI;Iyer R;Madge DJ;Jones HT;Cooper BR;Cox RF;Wang CM;Wiard RP Neuropharmacology. 1995 Feb;34(2):217-27.
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), and a novel inhibitor 709W92 ((E)-6-fluoro-3-[2-(4-pyridyl)vinyl]-1H-indole), of both TDO and 5-hydroxytryptamine (5-HT) reuptake, were examined on tryptophan catabolism, cerebrospinal fluid (CSF) concentrations of tryptophan and 5-HT and serotonergic-mediated physiology and behaviour in the rat. The catabolism of L-[ring-2-14C]tryptophan in vivo was completely inhibited by prior administration of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT depletion produced by p-chloroamphetamine and rapidly decreased dorsal raphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 260% of basal concentration. A maximally effective dose of 680C91 elevated a global measure of brain extracellular 5-HT (CSF 5-HT) to concentrations similar to those seen maximally after exogenous tryptophan administration (approx 170% of basal). Maximally effective doses of 709W92 increased CSF 5-HT to concentrations comparable to those seen after tryptophan and 5-HT reuptake inhibitor coadministration (approx 900% of basal) and to concentrations greater than those achieved maximally with serotonergically active antidepressant monotherapy (approx 500% of basal).
2.The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat.
Salter M;Hazelwood R;Pogson CI;Iyer R;Madge DJ Biochem Pharmacol. 1995 May 17;49(10):1435-42.
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 188.8.131.52), 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 184.108.40.206), 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.