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Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OXR) (K = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OXR, K = 1.36 nM; OXR, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OXR, which led to high OXR selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OXR antagonists.

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International audienceA diene-transmissive hetero-Diels–Alder reaction of cross-conjugated 1-azatrienes (3-1-azadendralenes) is described for the synthesis of hexahydroquinazolin-2-ones and hexahydrobenzothiazine-2-imines derivatives. [4+2] Cycloaddition reactions with tosyl isocyanate or aryl isothiocyanates gave mono-cycloadducts with high chemo- and regioselectivities. The second Diels–Alder reaction with representative dienophiles, tetracyanoethylene, N-phenylmaleimide, and methyl vinyl ketone, stereoselectively produced ring-fused nitrogen heterocycles. Skeletal diversity can be accessed by combining the three reaction partners – primary amine, tosyl isocyanate, and cross-conjugated 1-oxatriene – in a different sequential orde

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