Biology Reference
In-Depth Information
(Bailey et al.
1996
). CREB regulates a transcriptional cascade ultimately leading to
the remodeling of synaptic structure (Tully et al.
2003
).
6
Improved Tolerability of UCR2-Directed, PDE4
Allosteric Modulators
The emetic response to PDE4 inhibitors is mediated in part by a brainstem norad-
renergic pathway (Robichaud et al.
2001
) and tolerability can be improved by
limiting distribution to brain (Aoki et al.
2001
). Until recently, subtype selective
PDE4 inhibitors were not available, so it was not possible to link emesis with
inhibition of a particular PDE4 subtype. Although PDE4 gene-deleted mice have
been created by Conti and coworkers (Jin et al.
1999
; Jin and Conti
2002
), emesis
cannot be explored directly in mice. Unlike humans, rodents cannot relax their
crural sling, a band of muscles closing off the esophagus, while forcefully con-
tracting their diaphragm, so they are unable to vomit. Since vomiting cannot be
assessed directly, reduction of the duration of ketamine/xylazine anesthesia has
been introduced as a behavioral correlate of emesis that is sensitive to PDE4
inhibition (Robichaud et al.
2002a
). PDE4D null mice, but not PDE4B null mice
show a shortening of anesthesia duration in this test, suggesting that inhibition of
PDE4D may be the cause of emesis in nonrodent species (Robichaud et al.
2002b
).
This is in contrast to the emetic effect reported for highly selective PDE4D and
PDE4B inhibitors. Chambers et al. reported nicotinamide-based inhibitors that
are at least 25
selective for PDE4D (Chambers et al.
2006
), which later were
found to be emetic in animals and humans (unpublished). Naganuma et al. reported
2-arylpyrimidine-based inhibitors that are up to 100
selective for PDE4B; how-
ever, the lead compound was emetic in ferrets (Naganuma et al.
2009
). Transcripts
for both PDE4D and PDE4B can be detected in brainstem emetic centers of rodents
and human (Perez-Torres et al.
2000
), so the simple conclusion that inhibition of
PDE4D is the cause of emesis based on the Robichaud data in mice (Robichaud
et al.
2002b
) may not be correct.
We found it possible to design potent UCR2-directed compounds with high
selectivity for PDE4D (
100-fold). Comparing compounds with full and partial
inhibition of PDE4D, full inhibitors reduced anesthesia in the ketamine/xylazine
anesthesia test while partial inhibitors did not, even when dosed intravenously at a
1,000-fold greater dose than needed for procognitive benefit in the least sensitive
cognitive test (Burgin et al.
2010
). Emetic potential was investigated further in
Suncus murinus
(Asian house shrew), the beagle dog and cynomolgus monkey.
Suncus
have an emetic response to motion, ethanol overdose, and many classes
of drugs that are emetic in human (Ueno et al.
1987
; Hirose et al.
2007
). A UCR2-
directed,
>
100-fold selectivity for PDE4D over PDE4B
(D157140) caused emesis at 0.1 mg/kg, indicating that potent PDE4D inhibitors
are emetic (Robichaud et al.
2002b
). In contrast, the clinical lead compound,
full
inhibitor with
>
