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ACS Med Chem Lett. 2014 Jul 14;5(9):1032-6. doi: 10.1021/ml500241n. eCollection 2014 Sep 11.

Novel cyclic biphalin analogue with improved antinociceptive properties.

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Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio" , Via dei Vestini, 31, 66100 Chieti, Italy.
Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano, 49, 80131 Naples, Italy.
Dipartimento di Chimica, Sapienza, Università di Roma , P.le A. Moro, 5, 00187 Rome, Italy.
Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità , V.le Regina Elena 299, 00161 Rome, Italy.
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , 6726 Szeged, Hungary.
Department of Pharmacology and Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.


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 (K i (δ) = 5.2 nM; K i (μ) = 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.


Analgesics; biphalin; cyclic analogues; dimeric opioid peptides

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