Tryptophan-Containing Non-Cationizable Opioid Peptides – a new chemotype with unusual structure and in vivo activity

Abstract

Recently, a new family of opioid peptides containing tryptophan came to the spotlight for the absence of the fundamental protonable tyramine ‘message’ pharmacophore. Structure–activity relationship investigations led to diverse compounds, characterized by different selectivity profiles and agonist or antagonist effects. Substitution at the indole of Trp clearly impacted peripheral/central antinociceptivity. These peculiarities prompted to gather all the compounds in a new class, and to coin the definition ‘Tryptophan-Containing Non-Cationizable Opioid Peptides’, in short ‘TryCoNCOPs’. Molecular docking analysis suggested that the TryCoNCOPs can still interact with the receptors in an agonist-like fashion. However, most TryCoNCOPs showed significant differences between the in vitro and in vivo activities, suggesting that opioid activity may be elicited also via alternative mechanisms.