OPIOID RECEPTOR-TARGETING CYCLOPEPTIDES FOR PAIN MANAGEMENT: NEW STRUCTURES, NEW MECHANISMS

none3Despite substantial efforts by the pharmaceutical industry over the last decades, there has been little progress in developing new, efficacious and safe analgesics. However, in the last few years some atypical opioid compounds attracted considerable attention. Among them it is worth mention the KOR-selective hallucinogen Salvinorin A, the MOR-selective analogue of EM1 c[wFGYp] (cEM), the KOR-selective naturally occurring c[WFpF] (CJ-15,208), antagonist in vitro but agonist in vivo. These compounds appeared to activate the opioid receptors despite of the lack of the fundamental amino group pharmacophore. Objectives & Method. In particular, CJ-15,208 and cEM clearly show strikingly similar structures, albeit they show different pharmacological profiles. To investigate the role of the pharmacophores of the structurally related cyclopeptides, we synthesized and tested a verity of analogues. To determine the minimal bioactive sequence of this new class of opioid peptides, and to expand the scope of the novel opioid pharmacophore, we designed and tested the linear analogues Ac-wF-NH2, Ac-wFG-NH2. Results. Affinities and selectivity of the cyclic opioid peptides varied depending on the different 3D structures. Bioassays suggested that these compounds elicit in vivo analgesic activity via alternative or more complex mechanisms. The linear, minimalist sequences turned out as opioid ligands with nM affinity. Further, the introduction of alkyl groups and/or halogens onto the indole ring of Trp allowed to increase peptide lipophilicity and metabolic stability, therefore improving bioavailability and therapeutic efficacy. Conclusions. These results support the hypothesis that CJ-15,208 and cEM represent the first members of a new class of lipophilic opioid peptides; the Trp&Phe sequence constitutes an unusual kind of MOR pharmacophoric motif. Apparently, the stereochemistry and relative disposition of Trp and Phe, the macrocycle size, and secondary structure, strongly impact affinity and selectivity and agonism vs antagonism.noneR.de Marco; S.Spampinato; L. GentilucciR.de Marco; S.Spampinato; L. Gentilucc