Biomedical Engineering Reference
In-Depth Information
N
+
OH
H
N
+
N
O
N
O
OH
H
N
+
HO
O
N
+
N
+
N
H
N
N
Gallamine (
16.47
)
Alcuronium (
16.48
)
WIN 26,577 (
16.49
)
O
N
O
O
N
+
N
N
+
N
N
O
O
O
O
O
Brucine (
16.50
)
W84 (
16.51
)
FIGURE 16.10
Chemical structures of allosteric modulators of mAChRs.
Domains involved in
AC-42 binding
N
General allosteric site
Extracellular
TM 7
TM 6
Y408
Y381
W378
Y404
Intracellular
D105
Y106
Domains involved in
orthosteric ligand binding
TM 5
C
TM 3
(A)
(B)
FIGURE 16.11
(A) Binding mode of ACh to the orthosteric site of the M
1
mAChR (observed from the extra-
cellular side). (B) Localization of orthosteric and allosteric binding sites in the mAChR.
that is positively charged at physiological pH, and orthosteric ligand binding to the mAChR is cen-
tered in the ionic and cation-p interactions formed by this group to an aspartate residue in TM3
and aromatic residues in TM6 and TM7. This key interaction is supplemented by hydrogen bonds
and van der Waals interactions between residues in TM3, TM5, TM6, and TM7 of the mAChR and
other parts of the orthosteric ligand.
The wide range of structurally diverse allosteric mAChR modulators all seem to bind to a gen-
eral allosteric site localized just above the orthosteric site in the receptor, constituted by the upper
helix turns of the seven TMs and their three interconnecting extracellular loops (Figure 16.11B).
Finally, in agreement with its novel structure and selectivity proi le, the M
1
-selective agonist AC-42
has been demonstrated to bind to an allosteric site in this receptor composed of residues in amino-
terminal domain, TM1, and TM7 of the receptor (Figure 16.11B).
