Development of conformationally constrained linear peptides exhibiting a high affinity and pronounced selectivity for .delta. opioid receptors

Publisher Website
Google Scholar
Abstract
A series of linear conformationally constrained opioid peptides was designed in an attempt to develop highly selective and potent agonists for the .delta. opioid receptors. These enkephalin analogues corresponding to the general formula Tyr-D-X(OY)-Gly-Phe-Leu-Thr(OZ) were obtained by incorporating bulky residues (X = Ser or Thr; Y = tert-butyl or benzyl; Z = tert-butyl) into the sequence of the previously reported .delta. specific agonists DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr) and DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr). In binding studies based on displacement of .mu. and .delta. opioid receptor selective radiolabeled ligands from rat brain membranes, the two constrained hexapeptides, Tyr-D-Ser(O-t-Bu)-Gly-Phe-Leu-Thr (1, DSTBULET) (KI(.mu.) = 374 nM, KI(.delta.) = 6.14 nM, KI (.delta.)/KI(.mu.) = 0.016) and in particular Tyr-D-Ser(O-t-Bu)-Gly-Phe-Leu-Thr(O-t-Bu) (7, BUBU) (KI(.mu.) = 475 nM, KI (.delta.) = 4.68 nM, KI (.delta.)/KI(.mu.) = 0.010) were shown to be among the most potent and selective .delta. probes reported to date. A roughly similar pattern of selectivity was obtained with the guinea pig ileum and mouse vas deferens bioassays. In addition, the analgesic potency (hot-plate test) of these peptides intracerebroventricualrly administered in mice was shown to be significantly related to their .mu.-receptor affinity.