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

Research output: Contribution to journalJournal articleResearchpeer-review

Patrick R Gentry, Thomas M Bridges, Atin Lamsal, Paige N Vinson, Emery Smith, Peter Chase, Peter S Hodder, Julie L Engers, Colleen M Niswender, J Scott Daniels, P Jeffrey Conn, Michael R Wood, Craig W Lindsley

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.

Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Volume23
Issue number10
Pages (from-to)2996-3000
Number of pages5
ISSN0960-894X
DOIs
Publication statusPublished - 15 May 2013
Externally publishedYes

Bibliographical note

Copyright © 2013 Elsevier Ltd. All rights reserved.

    Research areas

  • Animals, Dose-Response Relationship, Drug, Drug Discovery, Humans, Indoles/chemical synthesis, Molecular Structure, Rats, Receptors, Muscarinic/metabolism, Structure-Activity Relationship

ID: 213625348