Design, Synthesis and Biological Evaluation of Novel Non-Peptide Opioid Ligands for Human Pain

Abstract

To find therapeutics for human pain with efficacy but without the side effects which accompany morphine-related drugs is a critical need. Based on extensive structure-activity studies of cyclic enkaphalins, we have designed and synthesized a series of conformationally constrained peptide analogues such as [(2S,3R)-TMT1]-DPDPE, which are essentially specific for the δ-opioid receptor [1]. Aiming to transfer the pharmacophores in these peptide ligands to a non-peptide scaffold and to maintain the high binding affinity and biological activities at the δ-receptor, first and second generation non-peptide ligands were successfully designed with the aid of computer modeling [2,3]. In an effort to optimize these ligands, we present some newly designed ligands such as 6–11 that are based on computer modeling and our understanding of current successful examples like SL-3111.