ArticleBioorganic & medicinal chemistry letters2015
Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.
Article in Bioorganic & medicinal chemistry letters, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
12 citing papers in PubMed.
- A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner .The Journal of pharmacology and experimental therapeutics · 2023Article
- Unified Approach to Diverse Fused Fragments via Catalytic Dehydrative Cyclization.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Identification of a Novel Allosteric Site at the MACS chemical neuroscience · 2021Article
- Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats.Neuropharmacology · 2020Article
- Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.Journal of medicinal chemistry · 2019Review
- 1-Aminobenzotriazole: A Mechanism-Based Cytochrome P450 Inhibitor and Probe of Cytochrome P450 Biology.Medicinal chemistry · 2018Article
- Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists.Bioorganic & medicinal chemistry letters · 2017Article
- Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.Bioorganic & medicinal chemistry letters · 2017Article
- Continued optimization of the MBioorganic & medicinal chemistry letters · 2017Article
- Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes.Bioorganic & medicinal chemistry letters · 2016Article
- Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.Chemical reviews · 2016Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors.
Funding
Abstract
This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.
Indexed as
Identifiers
What OpenQuestion holds
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.