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.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Michael S
authors: MS
authors: Poslusney
authors: Bruce J
authors: BJ
authors: Melancon
authors: Patrick R
authors: PR
authors: Gentry
authors: Douglas J
authors: DJ
authors: Sheffler
authors: Thomas M
authors: TM
authors: Bridges
authors: Thomas J
authors: TJ
authors: Utley
authors: J Scott
authors: JS
authors: Daniels
authors: Colleen M
authors: CM
authors: Niswender
authors: P Jeffrey
authors: PJ
authors: Conn
authors: Craig W
authors: CW
authors: Lindsley
authors: Michael R
authors: MR
authors: Wood
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D006801:Humans; D007510:Isatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: C581677:ML 137; D011759:Pyrrolidines; D043643:Receptor, Muscarinic M1; D013141:Spiro Compounds; D007510:Isatin; C032519:pyrrolidine