title: Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.
abstract: The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence.
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, United States.
authors.forename: Raveendra-Panickar
authors.initials: RP
authors.lastname: Dhanya
authors.forename: Shyama
authors.initials: S
authors.lastname: Sidique
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Hilary Highfield
authors.initials: HH
authors.lastname: Nickols
authors.forename: Ananda
authors.initials: A
authors.lastname: Herath
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Robert
authors.initials: R
authors.lastname: Ardecky
authors.forename: Svetlana
authors.initials: S
authors.lastname: Semenova
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002723:Chlorobenzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012646:Self Administration; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C562247:3-chloro-3'-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo(d)isothiazol-6-yloxy)methyl)biphenyl-4-carboxylic acid; D052160:Benzothiazoles; D002723:Chlorobenzoates; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D003042:Cocaine