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

Abstract

3(R)-(7a(S)-Hexahydro-l-oxo-3,3-dimethyl-1H-pyrrolo[1,2-c]imidazol-2-yl)-2-oxo-1-pyrrolidineacetamide (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. © 1994, American Chemical Society. All rights reserved.