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Vol. 299, Issue 1, 268-276, October 2001
ACADIA Pharmaceuticals Inc., San Diego, California (D.M.W., E.S.B.,
N.N., G.E.C., E.A.C., K.E.V., S.C.H., E.D., H.C.H., C.M.A., T.A.S.,
D.F.C.G., U.H., M.R.B.); and Departments of Neurosciences (D.M.W.),
Psychiatry (D.M.W., K.K., S.B.P., M.A.G.), and Pharmacology (M.R.B.),
University of California at San Diego, La Jolla, California
We have used a cell-based functional assay to define the
pharmacological profiles of a wide range of central nervous
system active compounds as agonists, competitive antagonists,
and inverse agonists at almost all known monoaminergic
G-protein-coupled receptor (GPCR) subtypes. Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are
potent competitive antagonists of the dopamine D2 receptor.
Surprisingly, this analysis also revealed that most are potent and
fully efficacious 5-hydroxytryptamine (5-HT)2A receptor
inverse agonists. No other molecular property was shared as universally
by this class of compounds. Furthermore, comparisons of receptor
potencies revealed that antipsychotics with the highest
extrapyramidal side effects (EPS) liability are significantly more
potent at D2 receptors, the EPS-sparing atypical agents had
relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors.
Functional high-throughput screening of a diverse chemical library
identified 530 ligands with inverse agonist activity at
5-HT2A receptors, including several series of compounds
related to known antipsychotics, as well as a number of novel
chemistries. An analog of one of the novel chemical series, AC-90179,
was pharmacologically profiled against the remaining monoaminergic
GPCRs and found to be a highly selective 5-HT2A receptor
inverse agonist. The behavioral pharmacology of AC-90179 is
characteristic of an atypical antipsychotic agent.
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