1. Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration
Jakub Fichna, et al. Bioorg Med Chem Lett. 2013 Dec 15;23(24):6673-6. doi: 10.1016/j.bmcl.2013.10.041. Epub 2013 Oct 30.
We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous μ-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a β-glycosidic bond. The improved blood-brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS.
2. Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges
Žiga Hodnik, Tihomir Tomašić, Lucija Peterlin Mašič, Fiona Chan, Robert W Kirby, David J Madge, Danijel Kikelj Eur J Med Chem. 2013;70:154-64. doi: 10.1016/j.ejmech.2013.07.034. Epub 2013 Aug 11.
Clathrodin, alkaloid isolated from Agelas sponges, was reported in 1995 as a voltage-gated sodium channel modulator. Here we describe the design and synthesis of conformationally restricted clathrodin analogues incorporating the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine moiety and evaluation of their modulatory activities on human voltage-gated sodium channel isoforms Na(v)1.3, Na(v)1.4 and Na(v)1.7, as well as their selectivity against cardiac isoform Na(v)1.5. Compounds were shown to act as state-dependent modulators of Na(v)1.3, Na(v)1.4 and Na(v)1.7 with IC₅₀ values in the lower micromolar range for the open-inactivated state of the channels. Preliminary structure-activity relationship studies have revealed the importance of hydrophobic interactions for binding to all three tested isoforms. Compound 4e with IC₅₀ value of 8 μM against Na(v)1.4 represents a novel selective state-dependent Na(v)1.4 channel modulator.
