G. A. Showell et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2555–2558
2557
phine, exacerbates emetic episodes. As numerous neuro-
nal pathways converge on the vomiting centre within the
brain new anti-emetics, operating by different mecha-
nisms of action may therefore provide an important
way forward in the future treatment of emesis.
In conclusion, (R)-2, a selective noradrenaline reuptake
inhibitor, has been demonstrated to effectively inhibit
emetic episodes caused by an emetogen, such as mor-
phine, in a well-characterized animal model. Its oral effi-
cacy in such a model suggests that compounds with this
mechanism of action may have clinical utility in the pre-
vention and treatment of PONV, particularly in settings
where morphine is used for post-operative pain relief.
More extensive pharmacological studies on (R)-2,
including other validated animal models of emesis, will
be presented in due course.
Figure 2. X-ray crystal structure of (R)-2 HBr. The silicon is green,
nitrogen is blue, and oxygen is red. The bromide atom has been
˚
omitted for clarity. The C–Si bonds within the ring are 1.85 A and the
sila-containing ring is more flattened than the equivalent cyclohexane
ring in 1 (see Ref. 7 for X-ray crystallography details and further
discussion).
Acknowledgments
The authors thank Professor Robert Naylor (University
of Bradford, UK) and Porsolt and Partners (Le Genest-
Saint-Isle, France) for in vivo studies, Ian Cooper
(Pharmorphix Ltd., Cambridge, UK) for physicochemi-
cal measurements on racemic 1 and 2, MDS Pharma
Services (Taiwan) and Cerep (France) for in vitro
100
90
80
70
60
50
40
30
20
10
0
assays, Dr. Christian Burschka (University of Wurz-
¨
burg, Germany) for X-ray crystallography studies,
Professor Paul Andrews (St. George’s Hospital Medical
School, London, UK), Dr. David Otway, Dr. Parminder
Pooni, Dr. David Miller and Dr. Chris Earnshaw
(Paradigm, Cambridge, UK) for helpful discussion.
1
5
50
Supplementary data
oral dose (mg/kg)
Figure 3. Anti-emetic profile of (R)-2 in a morphine-induced model of
emesis in the ferret. The test compound (R)-2 was dosed orally in
ferrets 2 h prior to the emetogen (morphine, 0.125 mg/kg, sc). Group
size, n = 4. The ferrets were monitored for emetic episodes for 2 h.
Supplementary data associated with this article can be
References and notes
2 displays a plasma half-life of 1.1 h with a Cmax of
225 ng/ml. At the 1 mg/kg dose, however, the compound
is virtually inactive and the emesis levels in the ferret are
comparable to morphine alone. In the same ferret emesis
model ondansetron,15 a marketed 5HT3 receptor antag-
onist anti-emetic agent, was evaluated and shows no ef-
fect (16 mg/kg) when administered orally.
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Emesis is a complex, multifactorial process for which,
presently, there is no therapeutic regime suitable for
treating all underlying biological emesis-related process-
es. The 5HT3 receptor has been identified as an impor-
tant receptor involved in the treatment of cancer
chemotherapy-related emesis, ondansetron being a key
therapeutic agent in use by oncology clinicians. Howev-
er other areas for treatment, such as post-operative nau-
sea and vomiting (PONV), are not well covered by
effective therapies. A number of post-operative factors
can influence the risk of PONV, and the relief of pain,
often associated with the use of opioids such as mor-