M. Froimowitz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3044–3047
3047
Figure 3. Stereoscopic image of the least squares superimposition of the crystal structure of 10c (blue) with the global minimum of threo-(R,R)-
methylphenidate (green).
corresponding atoms of the global minimum of threo-
(R,R)-methylphenidate (as represented by a 6-31G* ab
initio quantum mechanical calculation) in a least squares
sense, one again sees the close three dimensional corre-
spondence between the structures (Fig. 3), while the pres-
ence of the double bond in the vinylogous amides does
reduce the basicity of the amine group, it has been shown
that replacement of the nitrogen in methylphenidate by
either an oxygen or carbon atom does not preclude good
activity and that a basic nitrogen is not required for the
activity of methylphenidate analogs.15 Thus, the weak
activity of the vinylogous amides tends to cast doubt that
the biologically active conformer of threo-(R,R)-methyl-
phenidate is similar to the global minimum of the com-
pound. The intermediate 9a was also tested for activity
against the monoamine transporters since the boron-con-
taining rings also forces the compound into a similar con-
formation. However, this compound also proved to have
relatively weak activity, presumably due tothe presence of
the BF2 group.
Supplementary data
An experimental section is available as supplementary
material comprising experimental details for the synthe-
ses and crystallographic studies, combustion analyses,
and NMR, melting point, and crystallographic data.
Supplementary data associated with this article can be
References and notes
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Crystallographic data (excluding structure factors) for
structures 8a, 9a, 10a–10c in this letter have been depos-
ited with the Cambridge Crystallographic Data Centre
as supplementary publications numbers 256858, 256859,
255966, 255965, and 255964. Copies of the data can be ob-
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Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223-
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This work was supported by grant DA015795 from the
National Institute on Drug Abuse to M.F. X-ray crys-
tallographic studies were provided by contract Y1-
DA1002-04 from the National Institute on Drug Abuse.
Monoamine transporter binding and uptake studies
were provided by the Cocaine Treatment Discovery Pro-
gram, Division of Treatment Research and Develop-
ment, the National Institute on Drug Abuse under
contract Y1 DA 0107-05.