Non-peptide δ opioid agonists and antagonists

Following a flurry of medicinal chemistry activity in the late 1980s, a number of non-peptide pharmacological tools, selective for the δ opioid receptors, became available to challenge the pre-eminent position occupied by the existing peptide δ ligands. The first non-peptide δ antagonist NTI (1) represented a breakthrough in this field. Several analogues have been subsequently synthesised and are currently being used to clarify the pharmacology associated with the δ opioid receptors. The discovery of the selective δ agonists TAN-67 (50), BW373U86 (56) and SNC 80 (62) represented another step towards the understanding of the involvement of the δ opioid receptor in a number of possible pathophysiological conditions. This review addresses the recent highlights and developments that have been made by several research groups in the design of potent and selective non-peptide δ ligands. Focus has been given to the different pharmacological actions of δ agonists and antagonists. Analgesia can be considered the historical target for drugs acting through the opioidergic system. However, contrary to existing μ opioid narcotic drugs, there is substantial evidence to suggest that selective δ opioid agonists may be safe and effective analgesics. Beside this very important therapeutic target, recent studies have revealed that such drugs may elicit a variety of other beneficial pharmacological effects. They may also positively modulate some activities of μ agonists such as morphine. Animal models have demonstrated that δ antagonists may also play an important pharmacological role per se having possible clinical applications in preventing drug abuse, in organ transplantation and as antitussive agents.