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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.
AuthorsRaveendra-Panickar Dhanya, Shyama Sidique, Douglas J Sheffler, Hilary Highfield Nickols, Ananda Herath, Li Yang, Russell Dahl, Robert Ardecky, Svetlana Semenova, Athina Markou, P Jeffrey Conn, Nicholas D P Cosford
JournalJournal of medicinal chemistry (J Med Chem) Vol. 54 Issue 1 Pg. 342-53 (Jan 13 2011) ISSN: 1520-4804 [Electronic] United States
PMID21155570 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 3-chloro-3'-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo(d)isothiazol-6-yloxy)methyl)biphenyl-4-carboxylic acid
  • Benzothiazoles
  • Chlorobenzoates
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Cocaine
Topics
  • Administration, Oral
  • Allosteric Regulation
  • Animals
  • Benzothiazoles (chemical synthesis, pharmacokinetics, pharmacology)
  • Biological Availability
  • Brain (metabolism)
  • Chlorobenzoates (chemical synthesis, pharmacokinetics, pharmacology)
  • Cocaine (administration & dosage)
  • Cocaine-Related Disorders (drug therapy)
  • Drug Design
  • HEK293 Cells
  • Humans
  • Rats
  • Receptors, Metabotropic Glutamate (physiology)
  • Self Administration
  • Structure-Activity Relationship
  • Tissue Distribution

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