Discovery of ML326: The first sub-micromolar, selective M5 PAM
Research output: Contribution to journal › Journal article › Research › peer-review
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 language | English |
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Journal | Bioorganic & Medicinal Chemistry Letters |
Volume | 23 |
Issue number | 10 |
Pages (from-to) | 2996-3000 |
Number of pages | 5 |
ISSN | 0960-894X |
DOIs | |
Publication status | Published - 15 May 2013 |
Externally published | Yes |
Bibliographical note
Copyright © 2013 Elsevier Ltd. All rights reserved.
- Animals, Dose-Response Relationship, Drug, Drug Discovery, Humans, Indoles/chemical synthesis, Molecular Structure, Rats, Receptors, Muscarinic/metabolism, Structure-Activity Relationship
Research areas
ID: 213625348