Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule.

@article{Poslusney2013SpirocyclicRF,
  title={Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule.},
  author={M. Poslusney and Bruce J. Melancon and P. R. Gentry and D. Sheffler and T. M. Bridges and T. Utley and J. Daniels and C. Niswender and P. J. Conn and C. Lindsley and M. Wood},
  journal={Bioorganic & medicinal chemistry letters},
  year={2013},
  volume={23 6},
  pages={
          1860-4
        }
}
  • M. Poslusney, Bruce J. Melancon, +8 authors M. Wood
  • Published 2013
  • Chemistry, Medicine
  • Bioorganic & medicinal chemistry letters
    • This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6-membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype. 
    View on PubMed
    europepmc.org
    18 Citations
    Background Citations
    1

    Topics from this paper

    Explore Further: Topics Discussed in This Paper

    18 Citations
    Citation Type

    Citation Type

    Discovery of ML326: The first sub-micromolar, selective M5 PAM.
    • 12
    The use of spirocyclic scaffolds in drug discovery.
    • 261
    Access to highly enantioselective and diastereoselective spirooxindole dihydrofuran fused pyrazolones.
    • 3
    P(NMe2)3-mediated reductive [1+4] annulation of isatins with enones: a facile synthesis of spirooxindole-dihydrofurans.
    • 31
    • PDF
    Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity.
    • 21
    From (Phenylsulfanyl)cycloalkanecarbaldehydes to Optically Active Spirocyclic Tetrahydrofurans: Stereospecific Resolution of Symmetric Aldehydes through (S)‐Proline‐Catalysed Aldol Reaction
    • 9
    Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators.
    • 6
    N-1,2,3-triazole-isatin derivatives for cholinesterase and β-amyloid aggregation inhibition: A comprehensive bioassay study.
    • 2
    Organocatalytic asymmetric synthesis of dihydrofuran-spirooxindoles from benzylidene malononitriles and dioxindoles.
    • 4
    • PDF
    The Hypnotic, Anxiolytic, and Antinociceptive Profile of a Novel µ-Opioid Agonist
    • 9
    • PDF

    References

    SHOWING 1-10 OF 14 REFERENCES
    Isatin replacements applied to the highly selective, muscarinic M1 PAM ML137: continued optimization of an MLPCN probe molecule.
    • 16
    Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor.
    • 13
    Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.
    • 54
    Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor.
    • 26
    Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.
    • 75
    Formal dipolar cycloaddition of allylsilanes to o-quinonoid compounds: a convenient route to benzofused and spirofused heterocycles
    • 18
    Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM.
    • 41
    Centrally Active Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor Reverse Amphetamine-Induced Hyperlocomotor Activity in Rats
    • 155
    • PDF
    Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development
    • 489
    Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M4 Muscarinic Acetylcholine Receptor
    • 23