| Abstract
| - In the present study, the minimal fragment sequence required to fully activate the nociceptin(NC) receptor, namely NC(1−13)-NH2, was used as template for the design of a series of newcompounds. Changes were made in the N-terminal tetrapeptide Phe-Gly-Gly-Phe, which hasbeen shown to be essential for receptor occupation and activation. The new compounds weretested for their ability to inhibit the electrically evoked contraction of the mouse vas deferens,a pharmacological preparation sensitive to NC. Results obtained indicate that (a) thereplacement of Gly2 or Gly3 with an aromatic residue (Phe) of l or d chirality eliminates theability of the peptide to occupy the NC receptor; (b) the distance between Phe and Phe4 of NCappears to be critical, since any alteration of it leads to a marked decrease or a total eliminationof biological activity; and (c) the insertion of a pseudopeptide bond between Phe1 and Glymaintains affinity but eliminates the ability of the peptide to activate the NC receptor andleads to antagonism. The peptide [Phe1ψ(CH2−NH)Gly2]-NC(1−13)-NH2 acts as a selectiveNC receptor antagonist and is inactive on opioid receptors. The results summarized in thispaper confirm and extend our previous findings by showing that the structural requirementsfor NC binding to its receptor are clearly different from those of opioids; in addition, thisstructure−activity study has led to the identification of the first NC receptor selectiveantagonist.
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