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

Michael S Poslusney; Bruce J Melancon; Patrick R Gentry; Douglas J Sheffler; Thomas M Bridges; Thomas J Utley; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Michael R Wood

doi:10.1016/j.bmcl.2013.01.017

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

Michael S Poslusney, Bruce J Melancon, Patrick R Gentry, Douglas J Sheffler, Thomas M Bridges, Thomas J Utley, J Scott Daniels, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley, Michael R Wood

23 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	23
Issue number	6
Pages (from-to)	1860-4
Number of pages	5
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2013.01.017
Publication status	Published - 15 Mar 2013
Externally published	Yes

Keywords

Allosteric Regulation
Animals
Humans
Isatin/analogs & derivatives
Protein Binding
Pyrrolidines/chemical synthesis
Rats
Receptor, Muscarinic M1/antagonists & inhibitors
Spiro Compounds/chemistry
Structure-Activity Relationship

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10.1016/j.bmcl.2013.01.017

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Poslusney, M. S., Melancon, B. J., Gentry, P. R., Sheffler, D. J., Bridges, T. M., Utley, T. J., Daniels, J. S., Niswender, C. M., Conn, P. J., Lindsley, C. W., & Wood, M. R. (2013). Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule. Bioorganic & Medicinal Chemistry Letters, 23(6), 1860-4. https://doi.org/10.1016/j.bmcl.2013.01.017

Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule. / Poslusney, Michael S; Melancon, Bruce J; Gentry, Patrick R et al.
In: Bioorganic & Medicinal Chemistry Letters, Vol. 23, No. 6, 15.03.2013, p. 1860-4.

Research output: Contribution to journal › Journal article › Research › peer-review

Poslusney, MS, Melancon, BJ, Gentry, PR, Sheffler, DJ, Bridges, TM, Utley, TJ, Daniels, JS, Niswender, CM, Conn, PJ, Lindsley, CW & Wood, MR 2013, 'Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule', Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 6, pp. 1860-4. https://doi.org/10.1016/j.bmcl.2013.01.017

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abstract = "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.",

keywords = "Allosteric Regulation, Animals, Humans, Isatin/analogs & derivatives, Protein Binding, Pyrrolidines/chemical synthesis, Rats, Receptor, Muscarinic M1/antagonists & inhibitors, Spiro Compounds/chemistry, Structure-Activity Relationship",

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AU - Melancon, Bruce J

AU - Gentry, Patrick R

AU - Sheffler, Douglas J

AU - Bridges, Thomas M

AU - Utley, Thomas J

AU - Daniels, J Scott

AU - Niswender, Colleen M

AU - Conn, P Jeffrey

AU - Lindsley, Craig W

AU - Wood, Michael R

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KW - Allosteric Regulation

KW - Animals

KW - Humans

KW - Isatin/analogs & derivatives

KW - Protein Binding

KW - Pyrrolidines/chemical synthesis

KW - Rats

KW - Receptor, Muscarinic M1/antagonists & inhibitors

KW - Spiro Compounds/chemistry

KW - Structure-Activity Relationship

U2 - 10.1016/j.bmcl.2013.01.017

DO - 10.1016/j.bmcl.2013.01.017

M3 - Journal article

C2 - 23416001

SN - 0960-894X

VL - 23

SP - 1860

EP - 1864

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 6

ER -

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

Abstract

Keywords

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