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Discovery of ML326: The first sub-micromolar,selective M5 PAM |
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| Authors: | 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 |
| Institution: | 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA;4. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;5. Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA;6. Department of Molecular Therapeutics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA |
| 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 >10 μM) 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 409 nM and 500 nM, respectively) with excellent mAChR selectivity (M1–M4 EC50s >30 μM) and a robust 20-fold leftward shift of the ACh CRC. |
| Keywords: | Muscarinic acetylcholine receptors Positive allosteric modulator (PAM) ML326 |
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