- Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats
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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.
- Dhanya, Raveendra-Panickar,Sidique, Shyama,Sheffler, Douglas J.,Nickols, Hilary Highfield,Herath, Ananda,Yang, Li,Dahl, Russell,Ardecky, Robert,Semenova, Svetlana,Markou, Athina,Conn, P. Jeffrey,Cosford, Nicholas D. P.
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p. 342 - 353
(2011/03/18)
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- Effects of [(N-alkyl-1,3-dihydro-1-oxoisoindolin-5-yl)oxy]alkanoic acids on chloride transport in primary astroglial cultures
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It has been demonstrated that agents which inhibit chloride influx and, therefore, lower intracellular chloride levels in the astrocyte, a major cell type in the cerebral gray matter, inhibit astrocytic swelling in vitro and in vivo. Herein, we report additional examples of a series of [(N-alkyl-1,3- dihydro-1-oxoisoindolin-5-yl)oxy]alkanoic acids and their effects upon ion transport in primary rat astrocyte cultures. The 4-chloro-substituted 1- oxoisoindolines demonstrated superior astrocytic chloride influx inhibitory activity as compared to the 6-chloro and non-chlorinated analogs. The four- carbon acid side chain derivatives were more active than the three- and two- carbon analogs. The pharmacological profile of these compounds was examined with respect to inhibition of the Cl--Cl-/Cl--HCO3- anion exchanger and Na+-K+-2Cl cotransport mechanisms in glia, and the compounds were found to exhibit a similar profile to that of furosemide by inhibiting both transporters.
- Waller,Wyrick,Park,Kemp,Smith
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p. 571 - 576
(2007/10/02)
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