title: Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia.
abstract: Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human=106; rat=50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Uyen
authors.initials: U
authors.lastname: Le
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Melancon
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Utley
authors.forename: Atin
authors.initials: A
authors.lastname: Lamsal
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Daryl
authors.initials: D
authors.lastname: Venable
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
mesh_terms: D000494:Allosteric Regulation; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018678:Cholinergic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000737:chemistry / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000577:Amides; D018678:Cholinergic Agents; C581255:ML253; D011725:Pyridines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; C023666:pyridine