Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu(2/3)) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence

[Image: see text] 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 mGlu(2) receptor PAMs and no activity at mGlu(3). Compound optimization led to the identification of potent mGlu(2/3) selective PAMs with no in vitro activity at mGlu(1,4–8) or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu(2) and PAM activity at mGlu(3). The most potent mGlu(2/3) PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu(2/3) 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 mGlu(2/3) receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.