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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Bioorganic & Medicinal Chemistry Letters
Vol/bind	23
Udgave nummer	6
Sider (fra-til)	1860-4
Antal sider	5
ISSN	0960-894X
DOI	https://doi.org/10.1016/j.bmcl.2013.01.017
Status	Udgivet - 15 mar. 2013
Udgivet eksternt	Ja

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10.1016/j.bmcl.2013.01.017

Citationsformater

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.

I: Bioorganic & Medicinal Chemistry Letters, Bind 23, Nr. 6, 15.03.2013, s. 1860-4.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 23, nr. 6, s. 1860-4. https://doi.org/10.1016/j.bmcl.2013.01.017

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

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",

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

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doi = "10.1016/j.bmcl.2013.01.017",

language = "English",

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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

PY - 2013/3/15

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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

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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

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