A topographical model of mu-opioid and brain somatostatin receptor selective ligands. NMR and molecular dynamics studies.
We have refined the 1H NMR-based conformations of the mu-opioid receptor selective peptides related to somatostatin of general formula Xxx-Yyy1-Cys-Zzz-D-Trp-Lys(Orn)5-Thr-Pen-Thr8- NH2, where Xxx, Yyy, Zzz are 0, D-Phe and Tyr for 1; 0, D-Tic and Tyr for 2; Gly, D-Tic and Tyr for 3; and 0, D-Phe and Tic for 4, respectively, (Kazmierski et al., J. Am. Chem. 113, 2275-2283), using a molecular-dynamics approach. We present evidence that the NMR data are compatible with beta II'-, gamma- and gamma'-turns for the central tetrapeptide Tyr-D-Trp-Lys/Orn-Thr. Based on detailed structural and topographical considerations, we suggest that the mu-opioid receptor selectivity of 2 is due to a particular spatial arrangement of aromatic side chains of D-Tic1 and Tyr3 (7.5 A), and that the opioid receptor recognition domain is located in the N-terminal part of the peptide while the somatostatin receptor recognition domain is determined by the central, turn forming part of this class of cyclic peptides. A model for a mu-opioid selective ligand has emerged from these studies that shows excellent structural similarities to rigid opioid alkaloids.
Department of Chemistry, University of Arizona, Tucson, USA.
W M
WM
Kazmierski
R D
RD
Ferguson
A W
AW
Lipkowski
V J
VJ
Hruby
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D017450:Receptors, Opioid, mu; D017481:Receptors, Somatostatin; D013004:Somatostatin