ACS Medicinal Chemistry Letters
Page 4 of 6
compounds. This material is available free of charge via the
determined to have ED50 for SERT occupancy of 24
mg/kg, indicating that SERT target engagement in rat
was not significant at doses where robust P2X7 receptor
occupancy was observed.
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AUTHOR INFORMATION
Corresponding Author
Figure 3. Ex Vivo P2X7 Receptor Occupancy with
Compound 7 in Rat Brain: Dose Dependency Fol-
lowing Subcutaneous Administration (n = 3 per
dose ± SEM). P2X7 occupancy was measured 15
min after drug administration.
*Corresponding
author.
E-mail
address
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
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ABBREVIATIONS
IL-1β interleukin-1β, Bz-ATP benzoyl adenosine triphos-
phate, SERT serotonin transporter, DAT dopamine trans-
porter.
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20
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Figure 4. Ex Vivo P2X7 Receptor Occupancy with
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lowing Subcutaneous Administration (n = 3 per
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In conclusion, we have demonstrated that compounds 7
and 8 are high affinity rat, mouse and human P2X7 re-
ceptor antagonists and that both compounds have
DMPK properties suitable for pre-clinical pharmacody-
namics studies. At appropriate doses, both compounds
were shown to occupy central P2X7 receptors in vivo, as
assessed by ex-vivo autoradiography studies. Future
reports on the pharmacology of these interesting P2X7
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and related mood disorders.
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ASSOCIATED CONTENT
Supporting Information. Supporting information in-
cludes detailed synthetic procedures for all intermediates
and products and descriptions of assays used to characterize
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