CHARACTERIZATION OF THE BIOACTIVE FORM OF LINEAR PEPTIDE ANTAGONISTS AT THE DELTA-OPIOID RECEPTOR

The stereochemical requirements for delta-opioid receptor binding of a series of linear peptide antagonists with a novel conformationally re stricted Phe analogue (Tic) as a second residue were examined by using a variety of computational chemistry methods. The delta-opioid recept or analogues with significant affinity Tyr-Tic-NH2(TI-NH2), Tyr-Tic-Ph e-OH(TIP), Tyr-TiC-Phe-NH2 (TIP-NH2), Tyr-Tic-Phe-Phe-OH (TIPP), Tyr-T ic-Phe-Phe-NN2) (TIPP-NH2), and the low affinity delta-opioid peptides Tyr-Pro-Phe-Pro-NH2 (morphiceptin) and Tyr-Phe-Phe-Phe-NH2 (TPPP-NH2) , were included in this study. The conformational profiles of these pe ptides were obtained by consecutive cycles of high and low temperature molecular dynamic simulations, coupled to molecular mechanical energy minimization carried out until no new conformational minima were obta ined. Comparing the results for TPPP-NH2 and TIPP-NH2, the presence of the conformationally restricted Tic residue did not greatly reduce th e number of unique low energy conformations, but did allow low energy conformers involving cis bonds between the first st two residues. The conformational libraries of these peptides were examined for their abi lity to satisfy the three key ligand components for receptor recogniti on already identified by, previous studies of high affinity cyclic (Ty r(1)-D-Pen(2)-Gly(3)-Phe(4)-D-Pen(5)) enkephalin (DPDPE) type agonists . a protonated amine group, an aromatic ring, and a lipophilic moiety in a specific geometric arrangement. Two types of conformations common to the five high delta-opioid affinity L-Tic analogues were found tha t satisfied these requirements, one with a cis and the other with a tr ans peptide bond between the Tyr(1) and Tic(2) residues. Moreover, bot h the Tic(2) and Phe(3) residues could mimic the hydrophobic interacti ons with the receptor of the Phe(4) moiety in the cyclic DPDPE type ag onists, consistent with the appreciable affinity of both di- and tripe ptides. The low, delta-opioid receptor affinity of morphiceptin can be understood as the result of conformational preferences that prevent t he fulfillment of this pharmacophore for recognition. (C) 1996 John Wi ley & Sons, Inc.