Design, synthesis, X-ray analysis, and dopamine receptor-modulating activity of mimics of the 'C5' hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1- pyrrolidineacetamide

Article abstract of DOI:10.1021/jm00048a003

3(R)-(7a(S)-Hexahydro-1-oxo-3,3-dimethyl-1H-pyrrolo[1,2-c]imidazol-2-yl)- 2-oxo-1-pyrrolidine-acetamide (2) and 3(R)-[1-(2,5-dioxopyrrolidino[3,4- c]piperazino)]-2-oxo-1-pyrrolidineacetamide (3) were designed and prepared as mimics of the 'C5' hydrogen-bonded structure found in the crystal structure of 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide (1). Both compounds effectively restrict the ψ₁ torsional angle to very near the value found in the X-ray structure of 1 as seen in the X-ray crystallographic determination of 2 and methyl 3(R)-[1-(2,5-dioxopyrrolidino[3,4- c]piperazino)]-2-oxo-1-pyrrolidineacetate (11), a diketopiperazine intermediate in the synthesis of 3. These analogs were tested for their ability to enhance the binding of the dopamine D₂ receptor agonist N- propylnorapomorphine (NPA) in the absence and presence of 5'- guanylylimidodiphosphate (Gpp(NH)p). Both compounds enhanced [³H]-NPA binding in a dose-dependent manner by increasing both the binding affinity of the agonist and the number of high-affinity sites available for binding. Both 2 and 3 also attenuated the Gpp(NH)p-induced conversion of D₂ receptor high- affinity states to the low-affinity states.