Novel cyclic biphalin analogue with improved antinociceptive properties

  • ACS Med Chem Lett. 2014 Jul 14;5(9):1032-6. doi: 10.1021/ml500241n.
Adriano Mollica  1 ,  Alfonso Carotenuto  2 ,  Ettore Novellino  2 ,  Antonio Limatola  2 ,  Roberto Costante  1 ,  Francesco Pinnen  1 ,  Azzurra Stefanucci  3 ,  Stefano Pieretti  4 ,  Anna Borsodi  5 ,  Reza Samavati  5 ,  Ferenc Zador  5 ,  Sándor Benyhe  5 ,  Peg Davis  6 ,  Frank Porreca  6 ,  Victor J Hruby  6
Affiliations
  • 1. Dipartimento di Farmacia, Università di Chieti-Pescara "G. d'Annunzio" , Via dei Vestini, 31, 66100 Chieti, Italy.
  • 2. Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano, 49, 80131 Naples, Italy.
  • 3. Dipartimento di Chimica, Sapienza, Università di Roma , P.le A. Moro, 5, 00187 Rome, Italy.
  • 4. Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità , V.le Regina Elena 299, 00161 Rome, Italy.
  • 5. Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , 6726 Szeged, Hungary.
  • 6. Department of Pharmacology and Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
PMID: 25221662 DOI: 10.1021/ml500241n
Abstract

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.

Keywords
Analgesics; biphalin; cyclic analogues; dimeric opioid peptides.