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Vol. 61, Issue 1, 160-168, January 2002
Departments of Psychiatry and Pharmacology, Penn State
College of Medicine, Hershey Pennsylvania (S.B., J.E.); Departments of
Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn,
Bonn, Germany (S.B., K.M.); and Department of Pharmaceutical Chemistry,
Institute of Pharmacy, University of Würzburg, Würzburg,
Germany (D.P.Z.)
Diverse muscarinic allosteric ligands exhibit greatest affinity
toward the M2 receptor subtype and lowest affinity toward M5. In this study, we evaluated the potencies with which
two groups of highly M2/M5 selective allosteric
agents modulate the dissociation of
[3H]N-methylscopolamine from
M2/M5 chimeric and point-mutated receptors. These allosteric ligands included two alkane-bisammonium compounds and
a series of caracurine V derivatives, which are structurally closely
related to (but stereochemically different from) the prototype allosteric ligand alcuronium. Like alcuronium, the caracurine V and
alkane-bisammonium compounds displayed significantly increased affinities compared with M5 toward the chimera that
included the M2 second outer loop (o2) plus surrounding
regions. Unlike alcuronium, the compounds had enhanced affinities for a
chimera with M2 sequence in transmembrane region (TM) 7;
site-directed mutagenesis in wild-type and chimeric receptors indicated
that the threonine residue at M2423 was
entirely responsible for the sensitivity toward TM7. Subsequent studies
demonstrated that this TM7 epitope is likewise present in the
M4 receptor, as M4436serine. The
M2423threonine residue is near the
M2419asparagine identified previously to
influence gallamine binding. These studies demonstrate that a
stereochemical difference can be sufficient to translate into divergent
epitope sensitivities. Nonetheless, these allosteric ligands seem to
derive affinity from two main regions of the receptor: o2 plus flanking
regions and o3/TM7. These two epitopes are sufficient to explain the
M2/M5 selectivity of the presently investigated
compounds; this is the first time that the subtype selectivity of
muscarinic allosteric agents has been completely accounted for by
distinct receptor epitopes.
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