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lithium reagents in the final addition step. In this way,
the SAR of selective and metabolically stable GlyT1
inhibitors can be extensively explored.
In conclusion, introduction of a hydroxy group in posi-
tion 2 of the potent GlyT1 inhibitors 8-(2-aryl-cyclo-
hexyl)-1-aryl-1,3,8-triazaspiro[4.5]decan-4-ones had
a
considerable influence on the pharmacological profile
of such compounds, reducing, in particular, the affinity
towards the l and NOP receptors in the cis series. From
the stereochemical point of view, the relative 1,2 orienta-
tion showing the optimal profile is inverted with respect
to the non-hydroxy substituted derivatives. Synthetic
access to such compounds was amenable to parallel
synthesis, which allowed rapid exploration of the SAR
and modulation of the physicochemical properties. In
the N(1)-alkyl subset, introduction of the hydroxy group
brings about a notable metabolic stabilization, paving
the way for the identification of metabolically stable,
potent and selective GlyT1 antagonists.
8. Any data regarding the hNOP receptor mentioned in this
communication were generated in the years 2001 and
2002.
Acknowledgments
9. Unpublished results.
We thank Patrick Bourdeaux, Sylvia Meyer, Marianne
Rueher, Patrick Boissin, Serge Burner, and Daniel
Zimmerli for their dedicated technical assistance and
Robert Narquizian and Andrew Thomas for support
and advice.
10. Cells transfected with hGlyT-1b or hGlyT2 were seeded in
96-well culture plates. The cells were washed twice with
uptake buffer (UB) and then incubated for 30 min at 22 °C
with either (i) no potential competitor, (ii) 10 mM non-
radioactive glycine, or (iii) a test compound. A solution
was then immediately added containing [3H]glycine 60 nM
(11–16 Ci/mmol) and 25 lM non-radioactive glycine
(hGlyt1) or [3H]glycine 200 nM without cold glycine
(hGlyt2). The cells were then incubated with gentle
shaking for 30 min at 22–24 °C, after which the reaction
was stopped by aspiration of the mixture and washing
(three times) with ice-cold UB. The cells were lysed with
scintillation liquid, shaken for 3 h and the radioactivity in
the cells was counted using a scintillation counter.
11. Wichmann, J.; Adam, G.; Roever, S.; Hennig, M.;
Scalone, M.; Cesura, A. M.; Dautzenberg, F. M. Eur. J.
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