Conformation-activity relationships of cyclo-constrained micro/delta opioid agonists derived from the N-terminal tetrapeptide segment of dermorphin/deltorphin.
The N-terminal tetrapeptide segments of dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) and deltorphin (Tyr-D-Ala-Phe-Asp/Glu-Val-Val-Gly-NH(2)) are agonists at the opioid receptors micro and delta, respectively. [D-Arg(2), Lys(4)]-dermorphin-(1-4) amide (Tyr-D-Arg-Phe-Lys-NH(2), DALDA) and [Dmt(1)]DALDA (where Dmt is 2',6'-dimethyltyrosine) are among the most potent and selective micro-agonists reported to date, both in vitro (having picomolar micro receptor affinity) and in vivo. In this communication, conformation-activity studies of the following four cyclic analogs of DALDA are presented and discussed: the lead peptide S(2),S(4)-cyclo (Tyr-D-Cys-Phe-Cys-NH(2)), constrained by means of an S(4.2)--S(4.4) disulfide between Cys(2) and Cys(4); its two cis and trans C(4.2)--C(4.4)-olefinic dicarba analogs, and the product of saturation of them both. They are potent nonselective or moderately micro-selective opioid agonists in vitro.They have been synthesized and tested earlier [Berezowska I, Chung NN, Lemieux C, Wilkes BC, and Schiller PW, Acta Biochim Polon 53, 2006, 73-76]. We have studied their conformations using NMR and molecular dynamics. With major conformational constraints imposed by the 11-membered ring spanning residues 2-4, they show well defined conformations of this ring, while the exocylic Tyr(1) and Phe(3) side chains still have significant conformational freedom. The more active and selective micro versus delta disulfide and saturated dicarba agonists seem to have in common: (i) their ring structures more flexible than those of the other two and (ii) their ring structures similar to each other and more diverse than those in the other two. Given this and the small size of the peptides having confirmed bioactivity profiles, there is a chance that their conformations determined in solution approach receptor-bound conformations.
Rodziewicz-Motowidło
Sylwia
S
Faculty of Chemistry, University of Gdańsk, Sobieskiego 18, 80-952 Gdańsk, Poland. sylwia@chem.univ.gda.pl
Czaplewski
Cezary
C
Luczak
Sylwia
S
Ciarkowski
Jerzy
J
D003198:Computer Simulation; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D018847:Opioid Peptides / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000737:chemistry*; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; C059567:deltorphin; C030058:dermorphin