Selective non-peptide kappa opioid receptor agonists

This article provides an overview of the development of selective K-opioid receptor antagonists as potential analgesics and neuroprotective agents. An important milestone in defining the properties of a K-receptor agonist was the discovery of the N-(2-aminocyclo-hexyl)arylacetamide class of selective K-receptor agonist, of which U-50488 was the prototype structure. Most of the subsequently reported classes of K-receptor agonist have their origins in the ethylenediamine amide pharmacophore present in U-50488. These include direct modification of U-50488 itself, structural simplification, (acyclic systems) and modification of the cyclohexane framework (piperidines and piperazines). Such strategies have provided highly potent and selective K-receptor agonists: U-62066 (spiradoline), CI-977 (enadoline), ICI199441, ZT52656 and GR89696. The full clinical picture for K-receptor agonists as analgesics or neuroprotective agents has yet to become available but initial data highlight concerns regarding side-effects of sedation, diuresis and dysphoria. It may be that the emerging picture of K-receptor subtypes will provide new directions in further refining this activity profile.