A TOPOGRAPHICAL MODEL OF MU-OPIOID AND BRAIN SOMATOSTATIN RECEPTOR-SELECTIVE LIGANDS - NMR AND MOLECULAR-DYNAMICS STUDIES

We have refined the H-1 NMR-based conformations of the mu-opioid recep tor selective peptides related to somatostatin of general formula yy(1 )cys-Zzz-D-Trp-Lys(Orn)(5)-Thr-Pen-Thr(8)-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 fo r 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 pre sent evidence that NMR data are compatible with beta II'-, gamma- and gamma' -turns for the central tetrapeptide Tyr-D-Trp-Lys/Orn-Thr. Base d on detailed structural and topographical considerations, we suggest that the mu-opioid receptor selectivity of 2 is due to a particular sp atial arrangement of aromatic side chains of D-Tic(1) and Tyr(3) (7.5 Angstrom), 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-poioid selective ligan d has emerged from these studies that shows excellent structural simil arities to rigid opioid alkaloids. (C) Munksgaard 1995.