Nonpeptidic delta (delta) opioid agonists and antagonists of the diarylmethylpiperazine class: what have we learned?

The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of delta-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the delta opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective delta opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the delta opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic delta opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.