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A. Mitchinson et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3441–3444
combined with complete antagonism as measured in the
patch-clamp assay. Finally, introduction of a 2-pyridyl
group (13) led to a dramatic reduction in efficacy at both
subtypes, resulting in inverse agonism.
dihydropyrazolo[4,3-c]pyridin-3-ones has been opti-
mised for functional selectivity, leading to the synthesis
of 12. This compound has an excellent in vitro profile,
combining good affinity at GABAA receptor subtypes
with good partial agonism at a3 and complete antago-
nism at a1. The estimated receptor occupancy of 12 in
the mouse is comparable to that of CGS 17867A, whilst
its pharmacokinetic profile in the rat is superior. How-
ever, the low receptor occupancy of 12 in the rat pre-
cluded its further in vivo characterisation.
Table 3 shows the SAR for compounds with changes
made to the saturated ring of CGS 17867A. Contraction
to a five-membered ring (14) afforded a high affinity
ligand for both subtypes, but exhibited reduced efficacy
at a3. Expansion to a seven-membered ring (15) signif-
icantly increased the efficacy at a1 compared to CGS
17867A. Incorporating an oxygen (16) or sulfur atom
(17) into the saturated ring led to much reduced efficacy
at a3, thus removing most of the functional selectivity.
Good affinity was maintained when amines were intro-
duced to the ring (20, 21), indicating a potentially useful
space that could be further explored in this region of the
molecule. However, functional selectivity had been lost
for these compounds, with full agonism observed at
both subtypes. Incorporating an amide (22) gave
acceptable affinity, but the efficacy profile was now the
reverse of that required, with agonism at a1 and
antagonism at a3.
Acknowledgements
We thank Samantha Clark, Fahd Choudhry and Ben
Satelle for additional oocyte efficacy measurements, and
Desmond O’Connor for pharmacokinetic data.
References and notes
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€
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From the in vitro data, compound 12 looked to have the
best efficacy profile in the patch-clamp assay, combining
antagonism at a1 with partial agonism at a3. The
compound was therefore selected for further profiling
in vivo. Compound 12 was found to have excellent
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In conclusion, we have determined that CGS 17867A is
a functionally selective BZ binding site ligand on the
GABAA receptor, and this may explain its atypical
behavioural profile in vivo compared to classical BZs.
Taking CGS 17867A as a starting point, a series of 2,5-