title: Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors.
abstract: Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH(2)) showed potent binding and agonist activities at delta and mu opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Agnes
authors.forename: Jinfa
authors.initials: J
authors.lastname: Ying
authors.forename: Katalin E
authors.initials: KE
authors.lastname: Kövér
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Shou-wu
authors.initials: SW
authors.lastname: Ma
authors.forename: Hamid
authors.initials: H
authors.lastname: Badghisi
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009292:Narcotic Antagonists; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000037:antagonists & inhibitors; D011957:Receptors, Opioid / Q000819:agonists; D013329:Structure-Activity Relationship
chemical_list: D004220:Disulfides; D009292:Narcotic Antagonists; D010456:Peptides, Cyclic; D011949:Receptors, Cholecystokinin; D011957:Receptors, Opioid