Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.

Dhanya RP, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, Dahl R, Ardecky R, Semenova S, Markou A, Conn PJ, Cosford ND
J Med Chem. 2011 54 (1): 342-53

PMID: 21155570 · PMCID: PMC3071440 · DOI:10.1021/jm1012165

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.

MeSH Terms (17)

Administration, Oral Allosteric Regulation Animals Benzothiazoles Biological Availability Brain Chlorobenzoates Cocaine Cocaine-Related Disorders Drug Design HEK293 Cells Humans Rats Receptors, Metabotropic Glutamate Self Administration Structure-Activity Relationship Tissue Distribution

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