Benzocondensed derivatives as rigid analogues of the mu-opioid agonist 3(8)-cinnamyl-8(3)-propionyl-3,8-diazabicyclo[3.2.1]octanes: synthesis, modeling, and affinity

A new series of rigid analogues (1a-g, 2a-g) of the previously reported ana lgesic 3-cinnamyl-8-propionyl-3,8-diazabicyclo[3.2.1]octane (I) and its rev erted isomer 3-propionyl-8-cinnamyl (II) were synthesized, in which the cin namyl substituent is incorporated in benzocondensed bicyclic systems. Bindi ng assays for the affinity towards mu receptors indicated that, while in th e reverted series 2 the beta-naphthylmethyl (2d) and the benzocycloheptenyl methyl derivative (2g) favorably compared with II, all compounds 1 displaye d a mu-affinity lower than that of the parent I. Modeling studies suggest t hat the flexibility of the cinnamyl side chain plays an important role for activity. (C) 1998 Elsevier Science S.A. All rights reserved.