ArticleBioorganic & medicinal chemistry letters2013
Discovery of ML326: The first sub-micromolar, selective M5 PAM.
Article in Bioorganic & medicinal chemistry letters, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 29 citations in OpenAlex.
- The Novel Functions of M4 Muscarinic Receptors.Physiological research · 2025Review
- Cryo-EM reveals an extrahelical allosteric binding site at the MNature communications · 2025Article
- Multitargeting nature of muscarinic orthosteric agonists and antagonists.Frontiers in physiology · 2022Review
- Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.Journal of medicinal chemistry · 2019Review
- Discovery and Optimization of Potent and CNS Penetrant MACS chemical neuroscience · 2018Article
- Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.Cell · 2015Review
- Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.Bioorganic & medicinal chemistry letters · 2015Article
- Current approaches for the discovery of drugs that deter substance and drug abuse.Expert opinion on drug discovery · 2014Review
- Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).Journal of medicinal chemistry · 2014Article
- Article
- Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375).Journal of medicinal chemistry · 2013Article
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.