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Novel Cyclic Biphalin Analogue with Improved Antinociceptive Properties

Adriano Mollica, Alfonso Carotenuto, Ettore Novellino, Antonio Limatola, Roberto Costante, Francesco Pinnen, Azzurra Stefanucci,Stefano Pieretti, Anna Borsodi, Reza Samavati, Ferenc Zador, Sándor Benyhe, Peg Davis, Frank Porreca, and Victor J. Hruby, ACS Med. Chem. Lett., Article ASAP

Publication Date (Web): July 14, 2014

Copyright © 2014 American Chemical Society

Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2′ of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (Kiδ = 5.2 nM; Kiμ = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties.