title: Cyclic somatostatin octapeptide analogues with high affinity and selectivity toward mu opioid receptors.
abstract: A series of cyclic conformationally restricted penicillamine containing somatostatin octapeptide analogues have been prepared by standard solid phase synthetic techniques and tested for their ability to inhibit specific [125I]CGP 23,996 (des-Ala1-,Gly2-[desamino-Cys3Tyr11]-dicarba3, 14-somatostatin), [3H]naloxone or [3H]DPDPE ([D-Pen2-D-Pen5]enkephalin) binding in rat brain membrane preparations. We now report structure-activity relationship studies with the synthesis of our most potent and selective mu opioid receptor compound D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, which we refer to as Cys2Tyr3Orn5Pen7-amide. While this octapeptide exhibited high affinity (IC50 = 2.80 nM) for an apparently single population of binding sites (nH = 0.89 +/- 0.1) and exceptional selectivity for mu opioid receptors with an IC50(DPDPE)/IC50 (naloxone) ratio of 4,829, it also displayed very low affinity for somatostatin receptors (IC50 = 22,700 nM). Thus, Cys2Tyr3Orn5Pen7-amide may be the ligand of choice for further characterization of mu opioid receptors and for examining the physiological role of this class of receptors.
authors.forename: K
authors.initials: K
authors.lastname: Gulya
authors.forename: J T
authors.initials: JT
authors.lastname: Pelton
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: H I
authors.initials: HI
authors.lastname: Yamamura
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D009270:Naloxone / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D017481:Receptors, Somatostatin; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004745:Enkephalins; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D017481:Receptors, Somatostatin; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D009270:Naloxone; D013004:Somatostatin; C038136:CGP 23996; D020881:Enkephalin, D-Penicillamine (2,5)-