Rearrangement of 4,5α-epoxymorphinan derivatives with carbamoylepoxy rings provide novel oxazatricyclodecane structures

Novel Delta Opioid Receptor Agonists with Oxazatricyclodecane Structure

“…17 The synthesis and pharmacological characterization of DOR agonists with different chemotypes will help to better understand the different pharmacological profiles of distinct DOR agonists. We have recently reported the synthesis and binding affinities for the MOR, DOR, and KOR of an oxazatricyclodecane derivative 2a, which was obtained from endoethanotetrahydrothebaine derivative 1 by a novel rearrangement reaction 18 (Scheme 1). This new compound exhibited moderate affinities for the opioid receptors (K i (MOR) = 47.7 nM, K i (DOR) = 174.6 nM, and K i (KOR) =248.1 nM).…”

“…An equilibrium mixture of 2h and 7h was prepared from 5 by a previously reported method. 18 The mixture of 2g and 7g or 2h and 7h was reacted with CH 2 ClBr in the same manner shown in Scheme 2 to afford dioxymethylene compounds 3g,h. The 2-phenethyl group was introduced on the lactam nitrogen in 3g by alkylation to give 3i.…”

“…The synthesis of the objective compounds 4a , c – f commenced with compound 2a (Scheme ). The treatment of 2a with 2,2,2-trichloroethyl chloroformate (Troc-Cl) in the presence of K 2 CO 3 and the subsequent zinc/AcOH treatment gave norcompound 2b .…”

“…After a conversion of ester 5 into 6 , the treatment of 6 with t -BuOK in t -BuOH provided an equilibrium mixture of 2g and 7g . An equilibrium mixture of 2h and 7h was prepared from 5 by a previously reported method . The mixture of 2g and 7g or 2h and 7h was reacted with CH 2 ClBr in the same manner shown in Scheme to afford dioxymethylene compounds 3g , h .…”

“… a Binding assays were carried out in duplicate using mouse whole brain without cerebellum membranes for MOR and DOR or guinea pig cerebellum membranes for KOR. b [ 3 H] DAMGO was used. c [ 3 H] DPDPE was used. d [ 3 H] U-69,593 was used. e Ref . …”