Synthesis and biological activity of nociceptin/orphanin FQ(1–13)NH2 analogues modified in 9 and/or 13 position

The purpose of the present study was the synthesis and the biological screening of new analogues of N/OFQ(1–13)NH2, the minimal sequence maintaining the same activity as the natural peptide nociceptin. In order to investigate the role of Lys, we substituted Lys at positions 9 and/or 13 by Orn, Dab (diaminobutanoic acid) or Dap (diaminopropanoic acid). The new N/OFQ(1–13)NH2 analogues exerted strong and naloxone-resistant inhibition of electrically evoked contractions of rat vas deferens. Lys replacement with Orn maintained or even enhanced the inhibitory activity, while replacements with Dab and Dap decreased inhibitory activity.

H-Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-X9-Ser-Ala-Arg-X13-NH2X9,13 = Lys (1); X9 = Lys, X13 = Orn (2); X9 = Orn, X13 = Lys (3); X9,13 = Orn (4); X9,13 = Dab (5); X9,13 = Dap (6). The biological activities of the parent compound and its analogues were tested in vitro on electrically stimulated rat vas deferens.