DESIGN, SYNTHESIS, AND BIOLOGICAL PROPERTIES OF HIGHLY POTENT CYCLIC DYNORPHIN-A ANALOGS - ANALOGS CYCLIZED BETWEEN POSITION-5 AND POSITION-11

We have recently reported the synthesis of several cyclic disulfide br idge-containing peptide analogues of dynorphin A (Dyn A), which were c onformationally constrained in the putative address segment of the opi oid ligand. Several of these analogues, bridged between positions 5 an d 11 of Dyn A(1-11)-NH2, exhibited unexpected selectivities for the ka ppa and mu receptors of the central over the peripheral nervous system s. In order to further investigate the conformational and topographica l requirements for the residues in positions 5 and 11 of these analogu es, we have synthesized a systematic series of Dyn A(1-11)-NH2 analogu es incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides . In addition, Dyn A(1-11)-NH2, [D-Leu(5)]Dyn A(1-11)-NH2, and [D-Lys( 11)]Dyn A(1-11)-NH2 were synthesized as standards. Several of these cy clic analogues, especially c[Cys(5), D-Cys(11)] Dyn A(1-11)-NH2, c[Cys (5), L- or D-Pen(11)]Dyn A(1-11)-NH2, c[Pen(5), L-Pen(11)]Dyn A(1-11)- NH2 and c[Pen(5), L- or D-Cys(11)]Dyn A(1-11)-NH2, retained the same a ffinity and selectivity (vs the mu and delta receptors) as the parent compound Dyn A(1-11)-NH2 in the guinea pig brain (GPB). These same ana logues and most others exhibited a much lower activity in the guinea p ig ileum (GPI), thus leading to centrally vs peripherally selective pe ptides, but showed a different structure-activity relationship than fo und previously. In a wider scope, this series of analogues also provid ed new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at kappa opioid receptors. The results obtained in th e GPB suggest that requirements for binding are not the same for the k appa, mu, or delta central receptors.