A new generation of opioid peptidomimetics acting as central and/or peripheral analgesics

Generally, the most relevant cause of pain in patients with advanced stages of cancer tumour growth and the consequences on nervous structures. The tumoural mass and peritumour edema leads to a machanical stimulation of peripheral nociceptors, which is related to mediators released by the tumour, activating the firing of primary afferent neurons. Opioids acting at the CNS are the most powerful drugs for severe acute and chronic pain, but their widespread use is hampered by side effects such as depression of breathing, nausea, clouding of consciousness, constipation, addiction and tolerance. On the other hand, drugs which activate opioid receptors outside the CNS should be less potent but devoid of all centrally-mediated, unwanted effects. The endomorphins, (EM1, H-Tyr-Pro-Trp-PheNH2, EM2, H-Tyr-Pro-Phe-PheNH2) were isolated in 1997 by Zadina [1] from the mammalian brain, and were recognized as the most potent opioids against various forms of pain. EM derivatives have being studied worldwide to improve the pharmacokinetic features; in this constest, we recently synthesized and tested cyclic analogues deprived of the protonable amino group: c[Tyr-DPro-DTrp-Phe-Gly], c[Tyr-Gly-DTrp-Phe-Gly] and the correlated, non-EM-like c[D-Asp-1-amide-beta-Ala-D-Trp-Phe] [2]. These compounds showed nanomolar affinity and selectivity for MOR, and good in vivo antinociceptive activity towards visceral pain, and moderate efficacy in the tail flick test, suggestive of a partial penetration of the BBB. Molecular docking revealed that the primary pharmacophore interacting with the Asp147 of MOR is indole ring of D-Trp. Interestingly, these atypic EM analogues have a similar structure to that of CJ-15,208, isolated as a metabolite of a fungus, and its derivatives, Dolle 2009 [3], whose agonist activity has been discovered only very recently Aldrich 2011 [4]. To improve the central analgesia, we designed the linear peptide N-Ac-DTrp-Phe-GlyNH2, which maintained the nanomolar MOR affinity; the reduced size rendered the peptide more active in the tail-flick test. Modifications of the indole by halogenation/alkylation further improved the ability to cross the BBB