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Vol. 284, Issue 1, 291-297, 1998
The Laboratory of Cellular and Molecular Regulation and
**Laboratory of Cell Biology (M.B.), National Institute of Mental
Health, Bethesda, Maryland,
*Departments of Physiology and
Anesthesiology (K.P.M.), University of Washington, Seattle, Washington,
and
Eli Lilly Research Labs (C.C.F., K.J.F., G.J.C., D.C.H., D.W.J.,
M.O.C., G.A.K.), Neuroscience and Endocrine Divisions, Indianapolis,
Indiana
LY320135 is a selective antagonist for the brain CB1 receptor, having
greater than 70-fold higher affinity for the CB1 than the peripheral
CB2 receptor. The Ki values for
LY320135 at the CB1 and CB2 receptors, transfected and stably expressed in cell lines, were 224 nM and >10 µM, respectively. Similar
Ki values were measured in binding
studies performed on cerebellum and spleen membrane preparations
endogenously expressing the CB1 (203 nM) and CB2 (>10 µM) receptors,
respectively. LY320135 functionally reversed anandamide-mediated
adenylate cyclase inhibition in Chinese hamster ovary (CHO) cells
stably expressing the CB1 receptor. Pertussis toxin treatment of CHO
cells expressing the CB1 receptor attenuated the anandamide-mediated
inhibition of adenylate cyclase and unmasked a stimulatory effect of
anandamide on adenylate cyclase. The stimulatory component was blocked
with LY320135. This compound also blocked WIN 55212-2-mediated
inhibition of N-type calcium channels and activation of inwardly
rectifying potassium channels in N18 and AtT-20-CB2 cells,
respectively. LY320135 is a promising lead compound for the further
development of novel, potent and selective cannabinoid antagonists of
novel structure.
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