Opioid-substance P chimeric peptides

Abstract

ABSTRACT Chimerization of tachykinin and opioid pharmacophores offers a new avenue for analgesic development. The complexities of such design are illustrated by the analgesic efficacy (via different mechanisms) of chimeras that combine pharmacophores with opioid activity and substance P activity, as well as those that combine opioid agonist and substance P antagonist moieties. Although the interaction between substance P and opioid neural systems is more complex than a simple one-way inhibition, the relative balance of activities between tachykinin and opioid pharmacophores will generally determine the net effect of the chimeric molecule as pro-nociceptive, antinociceptive, or neutral. Intriguingly, endomorphins—μ-opioid receptor agonists with high intrinsic activity—may owe some of this high activity to weak but significant antagonist proper ties at tachykinin NK2 receptors, implying that these native peptides are endogenous chimeric opioid agonist–tachykinin antagonist compounds.