title: Structure-activity relationships of dynorphin analogs substituted in positions 2 and 3.
abstract: Following up on the observation that the dynorphin analog [Pro(3)]Dyn A(1-11)-NH(2) 2 possesses high affinity and selectivity for the kappa opioid receptor, a number of related peptides were prepared and characterized by radioligand binding and [(35)S]GTPgammaS assays. While incorporation of 2-azetidine carboxylic acid in position 3 led to the equally potent analog 3, the corresponding analog containing piperidine-2-carboxylic acid showed a nearly 90-fold reduction in kappa affinity. Differential preferred bond angles phi in the three building blocks might account for these observations. Compounds 2 and 3 were kappa antagonists with IC(50) values of 380 and 350 nM, respectively. The Sar(3) analog 7 and the Sar(2) analog 8 were kappa agonists, with greater selectivity than Dyn A(1-11)-NH(2) 1. In view of their high kappa affinities (8: K(i) = 1.5 nM; 2: K(i) = 2.4 nM), the new analogs were surprisingly weak kappa agonists or antagonists, e.g., the EC(50) value for the agonist 8 was 280 nM. Different kappa receptor subtypes in binding vs functional assays can not account for these results, since both assays were performed using the same membrane preparation.
authors.affiliation: University of California, San Diego, Department of Chemistry and Biochemistry, 9500 Gilman Drive, La Jolla 92093-0343, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Schlechtingen
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Daubert
authors.forename: Joel
authors.initials: J
authors.lastname: Cassel
authors.forename: Murray
authors.initials: M
authors.lastname: Goodman
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D004399:Dynorphins / Q000737:chemistry* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004399:Dynorphins