The
activity
and selectivity of the glut
am
ate receptor
ant
agonists belonging to the 2,3-benzodi
azepine cl
ass of compounds h
ave been ex
amined
at recombin
ant hum
an non-NMDA glut
am
ate receptors expressed in HEK293 cells
and on n
ative r
at NMDA
and non-NMDA receptors
in vitro. The r
acemic 2,3-benzodi
azepines GYK152466, LY293606 (GYKI53405)
and L
Y300168 (GYKI53655) inhibited AMPA (10 μM)-medi
ated responses in recombin
ant hum
an GluR1 receptors expressed in HEK293 cells with
approxim
ate ic
50 v
alues of 18 μM, 24 μM
and 6 μM, respectively
and AMPA (10 μM) responses in recombin
ant hum
an GluR4 expressing HEK293 cells with
approxim
ate ic
50 v
alues of 22 μM, 28 μM
and 5 μM, respectively. GYKI 52466, LY293606
and LY300168 were non-competitive
ant
agonists of AMPA receptor-medi
ated responses in
acutely isol
ated r
at cerebell
ar Purkinje neurons with
approxim
ate ic
50 v
alues of 10 μM, 8 μM
and 1.5 μM, respectively. The
activity of r
acemic compounds LY293606
and LY300168 w
as est
ablished to reside in the (−) isomer of e
ach compound. At
a concentr
ation of 100 μM, GYKI52466, LY293606
and LY300168 produced <30 % inhibition of k
ain
ate-
activ
ated currents evoked in HEK293 cells expressing either hum
an homomeric GluR5 or GluR6 receptors or heteromeric GluR6+KA2 k
ain
ate receptors. The
activity of the 2,3-benzodi
azepines
at 100 μM w
as we
ak
at k
ain
ate receptors, but w
as stereoselective. Simil
ar levels of inhibition were observed for k
ain
ate-induced currents in dors
al root g
anglion neurons. Int
act tissue prep
ar
ations were
also used to ex
amine the stereoselective
actions of the 2,3-benzodi
azepines. In the cortic
al wedge prep
ar
ation, the
active isomer of LY300168, LY303070, produced
a non-competitive
ant
agonism of AMPA-evoked depol
ariz
ations with sm
aller ch
anges in depol
ariz
ations induced by k
ain
ate
and no effect on NMDA-dependent depol
ariz
ations. LY303070 w
as
also effective in preventing 30 μM AMPA-induced depol
ariz
ations in isol
ated spin
al cord dors
al roots with
an
approxim
ate ic
50 v
alue of 1 μM. Syn
aptic tr
ansmission in the hemisected spin
al cord prep
ar
ation w
as stereoselectively
ant
agonized by the
active isomers of LY300168
and LY293606. In summ
ary, these results indic
ate th
at 2,3-benzodi
azepines
are potent, selective
and stereospecific
ant
agonists of the AMPA subtype of the non-NMDA glut
am
ate receptor. © 1997 Elsevier Science Ltd. All rights reserved.
align=""top""> ace=""arial"" size=""-1"" color=""black""> Publisher: | align=""top""> ace=""arial"" size=""-1"" color=""black""> Elsevier Science |
align=""top""> ace=""arial"" size=""-1"" color=""black""> Language of Publication: | align=""top""> ace=""arial"" size=""-1"" color=""black""> English |
align=""top""> ace=""arial"" size=""-1"" color=""black""> Item Identifier: | align=""top""> ace=""arial"" size=""-1"" color=""black""> S0028-3908(96)00156-6 |
align=""top""> ace=""arial"" size=""-1"" color=""black""> Publication Type: | align=""top""> ace=""arial"" size=""-1"" color=""black""> Article |
align=""top""> ace=""arial"" size=""-1"" color=""black""> ISSN: | align=""top""> ace=""arial"" size=""-1"" color=""black""> 0028-3908 |
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able>
| ace=""arial"" size=""-1"" color=""black""> Footnotes: <a name=""footnote_1"">The first two authors contributed equally to this work.
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