4 research outputs found
IMI â oral biopharmaceutics tools project â evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds
Dualsteric Muscarinic AntagonistsâOrthosteric Binding Pose Controls Allosteric Subtype Selectivity
Bivalent
ligands of G protein-coupled receptors have been shown
to simultaneously either bind to two adjacent receptors or to bridge
different parts of one receptor protein. Recently, we found that bivalent
agonists of muscarinic receptors can simultaneously occupy both the
orthosteric transmitter binding site and the allosteric vestibule
of the receptor protein. Such dualsteric agonists display a certain
extent of subtype selectivity, generate pathway-specific signaling,
and in addition may allow for designed partial agonism. Here, we want
to extend the concept to bivalent antagonism. Using the phthal- and
naphthalimide moieties, which bind to the allosteric, extracellular
site, and atropine or scopolamine as orthosteric building blocks,
both connected by a hexamethonium linker, we were able to prove a
bitopic binding mode of antagonist hybrids for the first time. This
is demonstrated by structureâactivity relationships, site-directed
mutagenesis, molecular docking studies, and molecular dynamics simulations.
Findings revealed that a difference in spatial orientation of the
orthosteric tropane moiety translates into a divergent M<sub>2</sub>/M<sub>5</sub> subtype selectivity of the corresponding bitopic hybrids