Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.
Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Akihiko S
AS
Kato
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Kevin D
KD
Burris
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Kevin M
KM
Gardinier
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Douglas L
DL
Gernert
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Warren J
WJ
Porter
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Jon
J
Reel
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Chunjin
C
Ding
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Yuan
Y
Tu
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Douglas A
DA
Schober
Applied Molecular Evolution, Eli Lilly and Company, San Diego, California, USA.
Matthew R
MR
Lee
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Beverly A
BA
Heinz
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Thomas E
TE
Fitch
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Scott D
SD
Gleason
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
John T
JT
Catlow
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Hong
H
Yu
Lilly UK, Eli Lilly and Company, Windlesham, UK.
Stephen M
SM
Fitzjohn
Lilly UK, Eli Lilly and Company, Windlesham, UK.
Francesca
F
Pasqui
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
He
H
Wang
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Yuewei
Y
Qian
Lilly UK, Eli Lilly and Company, Windlesham, UK.
Emanuele
E
Sher
Lilly UK, Eli Lilly and Company, Windlesham, UK.
Ruud
R
Zwart
Lilly UK, Eli Lilly and Company, Windlesham, UK.
Keith A
KA
Wafford
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Kurt
K
Rasmussen
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Paul L
PL
Ornstein
Lilly UK, Eli Lilly and Company, Windlesham, UK.
John T R
JT
Isaac
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Eric S
ES
Nisenbaum
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
David S
DS
Bredt
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.
Jeffrey M
JM
Witkin
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004244:Dizziness / Q000139:chemically induced; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D009570:Nitriles; D010433:Pentylenetetrazole / Q000633:toxicity; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011728:Pyridones / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy
D000927:Anticonvulsants; D052160:Benzothiazoles; C491911:Cacng2 protein, rat; D015220:Calcium Channels; D003292:Convulsants; C000621678:LY3130481; D009570:Nitriles; D011720:Pyrazoles; D011728:Pyridones; D018091:Receptors, AMPA; C515550:TARP gamma-8 protein, mouse; C588152:cacng8 protein, rat; C551441:perampanel; D010433:Pentylenetetrazole