Acetylcholine - Drug Design and Discovery - page 281

of the nAChRs possess a positively charged amino group, either in the form of a quaternary amino
group or a protonated tertiary or secondary amino group (Figures 16.13 and 16.14). This amino
group docks into an “aromatic box” formed by i ve aromatic residues facing the interface, pre-
dominantly from the a-subunit side, where the group forms a strong cation-p interaction with a
tryptophan (W) residue, while the other four aromatic residues ensures optimal spatial orientation
of the ligand for binding (exemplii ed by the agonist epibatidine and the competitive antagonist
MLA in Figure 16.16). The so-called complementary binding component, i.e., the interactions
between receptor and the rest of the ligand molecule, predominantly takes place to b-subunit side
of the orthosteric site (Figure 16.16). Since the i ve aromatic residues constituting the “primary
binding component” are highly conserved throughout the nAChR subunits, subtype-selectivity of
orthosteric ligands most often arise from this “complementary binding component.”
Galanthamine and physostigmine are believed to bind to an allosteric site in the amino-terminal
domain of the a-subunit in the nAChR complex, thereby increasing the receptors afi nity for the
orthosteric agonist and/or the probability of ion channel opening. The potentiation and inhibition of
nAChR signaling exerted by Ca 2+ and the Ab 42 peptide, respectively, also arise from binding to this
domain (Figure 16.16). Conversely, the noncompetitive antagonist mecamylamine ( 16.81 ) binds to a
site situated deep into the ion channel of the nAChR, where it blocks the inl ux of cations upon acti-
vation of the receptor. Finally, the modulation of nAChR function by steroids appears to originate
from a binding site involving the small extracellular carboxy-termini of the nAChR subunits.
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