Neuronal nico
tinic recep
tors (nAChRs) have been implica
ted in several diseases and disorders such as au
tism spec
trum disorders, Alzheimer鈥檚 disease, Parkinson鈥檚 disease, epilepsy, and nico
tine addic
tion. To unders
tand
the role of nAChRs in
these condi
tions, i
t would be beneficial
to have selec
tive molecules
tha
t targe
t specific nAChRs
in vitro and
in vivo. Our labora
tory has previously iden
tified a novel allos
teric si
te on human 伪4尾2 nAChRs using a series of compu
ta
tional and
in vitro approaches. A
t this si
te, we have iden
tified nega
tive allos
teric modula
tors
tha
t selec
tively inhibi
t human 伪4尾2 nAChRs, a sub
type implica
ted in nico
tine addic
tion. This s
tudy charac
terizes
the allos
teric si
te via si
te-direc
ted mu
tagenesis. Three amino acids (Phe118, Glu60, and Thr58) on
the 尾2 subuni
t were shown
to par
ticipa
te in
the inhibi
tory proper
ties of
the selec
tive an
tagonis
t KAB-18 and provided insigh
ts in
to i
ts an
tagonism of human 伪4尾2 nAChRs. SAR s
tudies wi
th KAB-18 analogues and various mu
tan
t 伪4尾2 nAChRs also provided informa
tion concerning how differen
t physiochemical fea
tures influence
the inhibi
tion of nAChRs
through
this allos
teric si
te. Toge
ther,
these s
tudies iden
tify
the amino acids
tha
t con
tribu
te
to
the selec
tive an
tagonism of human 伪4尾2 nAChRs a
t this allos
teric si
te. Finally,
these s
tudies define
the physiochemical fea
tures of ligands
tha
t influence in
terac
tion wi
th specific amino acids in
this allos
teric si
te.
Keywords:
thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=Negative+allosteric+modulator+%5C%28NAM%5C%29&qsSearchArea=searchText">Negative allosteric modulator (NAM); thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=neuronal+nicotinic+acetylcholine+receptors+%5C%28nAChRs%5C%29&qsSearchArea=searchText">neuronal nicotinic acetylcholine receptors (nAChRs); thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=%CE%B14%CE%B22&qsSearchArea=searchText">伪4尾2; thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=site%5C-directed+mutagenesis&qsSearchArea=searchText">site-directed mutagenesis; thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=structure%E2%88%92activity+relationships&qsSearchArea=searchText">structure鈭抋ctivity relationships; thors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=nicotine&qsSearchArea=searchText">nicotine