DYNORPHIN-(1-13) .1. STRUCTURE-FUNCTION-RELATIONSHIPS OF ALA-CONTAINING ANALOGS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 23  (4) , 361-367
Abstract
Dynorphin-(1-13) (Dyn-(1-13)) and its analogs substituted by single introduction of Ala in positions 1-11 were synthesized by the solid-phase method and purified by high pressure liquid chromatography. Relative potencies of the synthetic compounds were determined by their ability to inhibit electrically-evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with [3H]-etorphine for opiate receptors in rat brain homogenates. Introduction of Ala in positions 1 and 4 of Dyn-(1-13) provoked most important decreases in the activity of the molecule in the 3 assays (relative potency of 0.2% or less). Substitution of Ala in positions 2 or 5, but not 3, also severely decreased the potency of the peptide in the smooth muscle preparations (0.6-5.0% activity). However, the opiate receptor binding assay was less sensitive to the replacement of residue in position 2 (20% activity) than that in positions 3 or 5 (12 and 5% relative potencies, respectively). In the GPI assay and the opiate binding test, the other substitutions which greatly lowered the potency of the molecule were seen in positions 6, 7, 9 and 11, 4 basic residues. Among these, Arg6 and Arg7 were demonstrated to be the most important in the 3 biological tests. Finally, the replacement of Ile8 by Ala increased the relative potency of Dyn-(1-13) up to 191% and 900% in the MVD and the opiate binding tests, respectively.