J Pharmacol Exp Ther 2019 06 25;369(3):345-363. Epub 2019 Mar 25.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (K.L.K., R.M.A.S., W.G., B.L.A., K.M.G., D.L.G., P.L.O., W.P., J.R., C.D., H.W., Y.Q., K.D.B., A.N., V.B., S.S., J.C., J.M.W., K.-C.C., T.M.W., D.S., C.C.F., A.S.K., D.S.B., E.S.N.) and Lilly Research Centre, Eli Lilly and Company Ltd., Erl Wood Manor, Windlesham, Surrey, United Kingdom (R.Z., E.S.).
Nonselective glutamate -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) 8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of 8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant 8-containing AMPA receptors was modulated by coexpression with other TARPs; 2 subunits affected activity more than 3 subunits. Read More