TRYptophan-COntaining Non-Cationizable Opioid PeptideS (TRYCONCOPS): A new paradigm for opioid peptides

none5Despite of the current availability of new synthetic drugs, morphine and the other alkaloids found in the opium poppy plant still represent the drugs of choice for the relief of serious pain caused by cancer or other maladies. However, long-term usage is accompanied by severe side-effects such as respiratory depression, addiction liability, constipation, and tolerance. The discovery of the endogenous mammalian opioid peptides (enkephalins, dynorphins, endorphins, and endomorphins) increased expectations that painkillers devoid of side effects could be developed. Unfortunately, the clinical use of these endogenous peptides is prevented by their rapid degradation in vivo and their scarce permeation across the blood-brain barrier. The design of new drugs may now take advantage of the recent reports of the X-ray crystal structures of the opioid receptors complexed with selective ligands, a significant breakthrough in our understanding of the determinants of opioid ligand binding and selectivity. Nevertheless, this powerful approach does not explain the opioid behavior of compounds with atypical structure. Herein we discuss a new family of opioid peptides, the TRYptophan-COntaining Non-Cationizable Opioid PeptideS (TRYCONCOPS), peptides lacking the tyramine pharmacophore, which is fundamental for ligand-receptor interaction. The structurally related macrocyclic peptides c[YpwFG] and c[FpWF] (CJ-15,208) showed potent in vivo analgesic activity. Among the many derivatives, c[YGwFG] showed highly improved -opioid receptor affinity and maintained the agonists profile, and the tripeptide Ac-wFG-NH2 was recognized as the minimal active structure. The introduction of different substituents at the indole of D-Trp significantly influenced receptor affinities, and resulted in serum stability, and in a measurable effect on central antinociception in vivo after peripheral administration. Apparently, the TRYCONCOPS interact and activate the opioid receptors by alternative mechanism(s) respect to the classic opiates. Studies are currently in progress to understand these mechanisms, aiming at identifying novel opioids that could have significant advantages over existing drugs.noneR. De Marco; R. Artali; S. Spampinato; A. Bedini; L. GentilucciR. De Marco; R. Artali; S. Spampinato; A. Bedini; L. Gentilucc