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

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
Bioorg Med Chem Lett. 2013 23 (10): 2996-3000

PMID: 23562060 · PMCID: PMC3634896 · DOI:10.1016/j.bmcl.2013.03.032

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.

Copyright © 2013 Elsevier Ltd. All rights reserved.

MeSH Terms (9)

Animals Dose-Response Relationship, Drug Drug Discovery Humans Indoles Molecular Structure Rats Receptors, Muscarinic Structure-Activity Relationship

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