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Vol. 61, Issue 6, 1297-1302, June 2002
ACADIA Pharmaceuticals, Inc., San Diego, California (T.A.S., C.T.,
N.S., T.L.M., E.A.C., E.S.B., D.L., U.H., M.R.B.); and Department of
Pharmacology, University of California at San Diego, San Diego,
California (M.R.B.)
Receptors have well-conserved regions that are recognized and activated
by hormones and neurotransmitters. Most drugs bind to these sites and
mimic or block the action of the native ligands. Using a
high-throughput functional screen, we identified a potent and selective
M1 muscarinic receptor agonist from a novel structural class. Using a series of chimeric receptors, we demonstrated that this
ligand activates the receptor through a region that is not conserved
among receptor subtypes, explaining its unprecedented selectivity. This
region of the receptor is distinct from the conserved region that is
recognized by traditional ligands. The finding that receptors for
small-molecule transmitters can have multiple, structurally distinct
activation sites has broad implications for the study of receptor
structure/function and the potential for the discovery of novel ligands
with high selectivity.
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