title: Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor.
abstract: This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M(1) mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APPα release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Melancon
authors.forename: Rocco D
authors.initials: RD
authors.lastname: Gogliotti
authors.forename: James C
authors.initials: JC
authors.lastname: Tarr
authors.forename: Sam A
authors.initials: SA
authors.lastname: Saleh
authors.forename: Brian A
authors.initials: BA
authors.lastname: Chauder
authors.forename: Evan P
authors.initials: EP
authors.lastname: Lebois
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Utley
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
mesh_terms: D006801:Humans; D015335:Molecular Probes; D011976:Receptors, Muscarinic / Q000187:drug effects*
chemical_list: D015335:Molecular Probes; D011976:Receptors, Muscarinic