Non-peptide delta 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 delta opioid receptors, became available to challenge the pre-eminent position occupied by the existing peptide delta ligands. The first non-peptide delta 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 delta opioid receptors. The discovery of the selective delta agonists TAN-67 (50), BW373U86 (56) and SNC 80 (62) represented another step towards the understanding of the involvement of the delta 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 delta ligands. Focus has been given to the different pharmacological actions of delta agonists and antagonists. Analgesia can be considered the historical target for drugs acting through the opioidergic system. However, contrary to existing mu opioid narcotic drugs, there is substantial evidence to suggest that selective delta 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 mu agonists such as morphine. Animal models have demonstrated that delta 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.