Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities

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Abstract

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 24 lacking the dioxamethylene moiety. As we expected, the designed compounds 24 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.

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Acknowledgments

This work was partly supported by Adaptable and Seamless Technology Transfer Program through target-driven R&D, JST (AS2315040G). We also acknowledge the Institute of Instrumental Analysis of Kitasato University, School of Pharmacy for its facilities.

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