Design and synthesis of systemically active metabotropic glutamate subtype-2 and -3 (mGlu2/3) receptor positive allosteric modulators (PAMs): pharmacological characterization and assessment in a rat model of cocaine dependence.

Dhanya RP, Sheffler DJ, Dahl R, Davis M, Lee PS, Yang L, Nickols HH, Cho HP, Smith LH, D'Souza MS, Conn PJ, Der-Avakian A, Markou A, Cosford ND
J Med Chem. 2014 57 (10): 4154-72

PMID: 24735492 · PMCID: PMC4033659 · DOI:10.1021/jm5000563

As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure-activity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu2 receptor PAMs and no activity at mGlu3. Compound optimization led to the identification of potent mGlu2/3 selective PAMs with no in vitro activity at mGlu1,4-8 or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu2 and PAM activity at mGlu3. The most potent mGlu2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu2/3 PAMs. On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu2/3 receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.

MeSH Terms (12)

Allosteric Regulation Animals Cocaine-Related Disorders Disease Models, Animal Dose-Response Relationship, Drug Drug Design HEK293 Cells Humans Male Rats Rats, Wistar Receptors, Metabotropic Glutamate

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