title: Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: structure-activity relationships and assessment in a rat model of nicotine dependence.
abstract: Compounds that modulate metabotropic glutamate subtype 2 (mGlu(2)) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu(2) receptor positive allosteric modulators (PAMs). The effects of N-substitution (R(1)) and substitutions on the aryl ring (R(2)) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu(2) receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.
authors.affiliation: Apoptosis and Cell Death Research Program, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Shyama
authors.initials: S
authors.lastname: Sidique
authors.forename: Raveendra-Panickar
authors.initials: RP
authors.lastname: Dhanya
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Hilary Highfield
authors.initials: HH
authors.lastname: Nickols
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Arianna
authors.initials: A
authors.lastname: Mangravita-Novo
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.forename: Manoranjan S
authors.initials: MS
authors.lastname: D'Souza
authors.forename: Svetlana
authors.initials: S
authors.lastname: Semenova
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009538:Nicotine / Q000008:administration & dosage; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D007211:Indoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid; D009538:Nicotine