Biomedical Engineering Reference
In-Depth Information
OH
N
N
O
N
N
O
O
O
O
N
O
CPCCOEt (
15.110
)
BAY36-7620 (
15.111
)
EM-TBPC (
15.112
)
S
N
N
N
N
SIB-1893 (
15.113
)
MPEP (
15.114
)
MTEP (
15.115
)
FIGURE 15.22
Structures of some noncompetitive mGluR antagonists and positive allosteric modulators.
15.9 DESIGN OF DIMERIC POSITIVE AMPA RECEPTOR MODULATORS
Many receptors, including the Glu receptors, exist as dimers or higher oligomers and this creates the
possibility of having ligand-dimers, which can bind to two binding sites simultaneously. Dimeric
ligands have been developed in many different receptor areas and have led to compounds with not
only improved potency, but also improved selectivity, solubility, and pharmacokinetic properties
can be observed. In spite of numerous examples of dimeric ligands with improved pharmacology
compared to their monomeric analogs, no structural evidence have previously been presented for
the simultaneous binding of such ligands to two identical binding sites. However, such evidence
have been obtained for a dimeric positive allosteric modulator at AMPA receptors.
CTZ (
15.80
), see Section 15.7.7, is a positive allosteric modulator at AMPA receptors and an
x-ray structure of CTZ in complex with the GluR2-binding construct showed a symmetrical bind-
ing of two CTZ molecules in two identical binding sites close to each other. Another study showed
a number of biarylpropylsulfonamide analogs (
15.116
) with good activity as positive modulators
at the CTZ site, and these structures were used as templates for the design of a symmetrical
dimeric ligand. By use of computer modeling, different symmetric dimeric ligands with two pro-
pylsulfonamide moieties, a biphenyl linker, and different alkyl substituents were constructed and
tested for binding by computer docking. This led to the proposal of dimer
15.118
as a potential
ligand to bind, in a symmetrical mode, to two adjacent CTZ-binding sites, with an expected afi n-
ity three orders of magnitude better than the monomeric ligand
15.117
. Upon synthesis of the
two enantiomers of monomer
15.117
and the three stereoisomers of the dimer
15.118
(
R
,
R-
,
S
,
S
-,
and mesoform), these were tested for activity at cloned AMPA receptors expressed in oocytes
by electrophysiological experiments. (
R
,
R
)-
15.118
proved to be the most potent compound with
EC
50
= 0.79
M for the monomer (
R
)-
15.117
. The maxi-
mal potentiation of Glu responses for the monomer as well as for the dimer was in the order of
800%-1000%, showing that they are both effective potentiators by blockade of AMPA receptor
desensitization. Obviously the dimeric compound was dramatically more potent than the mono-
mer, more than three orders of magnitude, and a similar pattern was observed for the other less
active enantiomer (Figure 15.23).
In addition to this was (
R
,
R
)-
15.118
cocrystallized with the GluR2-binding construct, and from
the obtained x-ray structure it was shown that (
R
,
R
)-
15.118
simultaneously binds to two identical
modulatory binding sites at the AMPA receptors. This is shown in Figure 15.24 illustrating the
binding of (
R
,
R
)-
15.118
in comparison with two molecules of CTZ proving the simultaneous binding
of a dimeric ligand to two identical binding sites.
μ
M at GluR2 compared to EC
50
= 1980
μ
