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.
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). 709W92 did not elevate CSF 5-HT to concentrations associated with the serotonin syndrome (approx 3000% of basal). The combined TDO inhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activity in the rat-pup vocalization model of anxiety. These results show that 709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can produce an elevation of CSF 5-HT similar to that achieved with a serotonin reuptake inhibitor/tryptophan combination therapy but with a more sustained timecourse; such compounds may therefore have superior antidepressant efficacy in the clinic.
Salter
M
M
Wellcome Research Laboratories, Langley Court, Beckenham, U.K.
Hazelwood
R
R
Pogson
C I
CI
Iyer
R
R
Madge
D J
DJ
Jones
H T
HT
Cooper
B R
BR
Cox
R F
RF
Wang
C M
CM
Wiard
R P
RP
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors; D014364:Tryptophan / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007211:Indoles; C093792:TDO inhibitor LM10; D005473:Fluoxetine; D012701:Serotonin; D014364:Tryptophan; D010293:Pargyline