Discovery of ML326: The first sub-micromolar, selective M5 PAM.

Authors :: Gentry PR
Bridges TM
Lamsal A
Vinson PN
Smith E
Chase P
Hodder PS
Engers JL
Niswender CM
Daniels JS
Conn PJ
Wood MR
Lindsley CW
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 May 15; Vol. 23 (10), pp. 2996-3000. Date of Electronic Publication: 2013 Mar 16.
Publication Year :: 2013
Abstract: This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)