A. Brown et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2007–2009
2009
screened in an hGlyT-1b assay. None of the compounds
showed appreciable activity.
The possible association of GlyT-1 and NMDA recep-
tors may afford an opportunity for inhibition of the
transporter to enhance NMDA receptor function
through elevated concentrations of the co-agonist gly-
cine. This mechanism may have relevance in addres-
sing hypoglutamatergic function associated with
psychosis.
Interestingly, an N-acetic acid compound (Org 24461),
derived from the serotonin uptake inhibitor fluoxetine,
proved to be active with pIC50 6.5.
The Org 24461 series is highly sensitive to changes to the
a-amino acid (glycine) part of the molecule (Table 1).
The propionic and butyric acid homologues are inac-
tive. Changing N–CH3 to N–C2H5 loses activity. The
oxygen atom of the phenoxy ring system contributes to
binding but is not essential. Replacement with CH2
reduces activity by 0.5 log unit.
Electronic, lipophilic and geometric factors are all
involved in the interaction of these molecules with the
transporter (Table 2).
Activity is associated with an electron-withdrawing,
lipophilic group on the phenoxy ring:
Acknowledgements
4-CF3 ꢀ 3-CF3; 4-Cl ꢀ 3; 4-Cl2 > 4-Cl > 4-CH3
ꢀ OCH3 > 4-CH3SO2
During the course of this work, some of the compounds
in the series mentioned here, including Org 24598, were
claimed for glycine uptake inhibition (GUI) activity in
two patent applications in the name of Trophix Phar-
maceuticals Inc. These are WO 9745115 (Dec 04, 1997)
and WO 9745423 (Dec 04, 1997). To date, details of the
method of discovery or of SARs in the series have not
been published.
This region of the molecule is associated with a lipo-
philic cavity in the transporter which can accommodate
bulky groups such as 4-CH(CH3)3 and 4-Ph which con-
tribute to binding.
Ortho substitution on the phenoxy ring greatly reduces
binding, probably due to major steric/geometric effects
related to how the di-aryl system binds to the transpor-
ter. Meta substitution on the phenoxy ring also reduces
activity but not to the same extent.
References and Notes
Modest increases in activity are associated with an elec-
tron-withdrawing group on the other phenyl ring. Sub-
stitution with an electron-donating group is
accommodated with a slight reduction in activity.
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These findings, taken together, support the view that
some of the most extremely important molecular prop-
erties (such as geometric factors) for inhibiting the
GlyT-1 transporter are highly discriminating and, para-
doxically, are not included in diversity calculations.
Org 24598, the R-(À) isomer of Org 24461, is a highly
selective inhibitor of hGlyT-1b with negligible action at
GlyT-2 and other transporters and receptors. The com-
pound is approximately 600Â more potent than sarcosine.
13. Morrow, J. A.; Collie, I. T.; Dunbar, D. R.; Walker,
G. B.; Shahid, M.; Hill, D. R. FEBS Lett. 1998, 439 (3),
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