Discovery of dihydropyrazino-benzimidazole derivatives as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs).

A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure−activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies. Image 1 • A novel series of dihydropyrazino-benzimidazoles in search of mGluR2 PAMs were discovered as potential antipsychotics. • Pharmacophore guided structure−activity relationship studies resulted in potent and metabolically stable mGluR2 PAMs. • Compound 95 showed the most balanced profile. • Compound 95 demonstrated efficacy in the PCP-induced hyperlocomotion model in mice. [ABSTRACT FROM AUTHOR]