Design and synthesis of fused azacyclic and azaspirocyclic -lactams targeting dopaminergic D2/D4 receptors

The synthesis of fused azabicyclic and azaspirobicyclic gamma-lactams corresponding to tetrahydro-1H-pyrrolo[3,4-c] pyrrol-4-one and 2,7-diazaspiro[4.4]nonane-1-one core structures respectively containing a variety of N-aryl substituents is described as potential agonists of the dopaminergic D2/D4 receptors. Using the risperidone/DRD2 crystal structure data, we performed docking studies on a prototypical synthetic fused azabicyclic gamma-lactam, and the known D2 receptor ligand 1-(2-methoxyphenyl)-4-propylpiperazine. The racemic or enantiopure tosylate salts in the fused azabicyclic gamma-lactam series were found to be devoid of activity ((<= 10 % inhibition for either receptor at 0.1 mu M). However, marginal activity was expressed by the azaspirobicyclic gamma-lactam series against the D4 receptor albeit at 10 mu M with favorable ADME properties. The fused and spiroazabicyclic gamma-lactam core structures are interesting ring-constrained piperazines for further diversification in the context of medicinally relevant programs.