Novel approaches to targeting neuropeptide systems.

Generation and/or interruption of cell signalling by neuropeptides has been shown to be essentially, although not exclusively, mediated by one or several membrane-bound enzymes, giving rise to the concept of selective versus dual enzyme inhibitors. Because most of these enzymes are zinc metallopeptidases, novel inhibitors are now being designed based on the structure of these proteins. The physiological role of neuropeptides and their relationships with other peptide systems can be investigated by comparing results obtained using peptidase inhibitors and selective receptor antagonists with those obtained using mice in which genes encoding the various components of a peptide system have been deleted. The potential use of peptidase inhibitors, compared with exogenous agonists, as therapeutic agents (particularly as analgesics or antidepressants) and their use in the investigation of the neurobiology of drug abuse will be discussed with particular focus on enkephalins and cholecystokinin 8 (CCK-8).