High affinity conformationally constrained nociceptin/orphanin FQ(1-13) amide analogues

A series of cyclic analogues with a lactam linkage were prepared by solid phase peptide synthesis to explore possible biologically active conformatioms) of nociceptin/orphanin FQ (N/OFQ). CyC1o[D-ASp7,l_ys1o]- and cyclo[ASp6,l_ys'0lN/OFQ(l-l3)NH2 exhibit high affinity (Ki = 0.27 and 0.34 nM, respectively) and high potency in the GTPyS assay (EC50 = 1.6 and 4.1 nM, respectively) at human nociceptin/orphanin FQ peptide (NOP) receptors. These analogues exhibit 2- to 3-fold higher affinity and 2- to 5-fold higher potency than the parent peptide.