THE MU-OPIOID RECEPTOR-BINDING PHARMACOPHORE CONFORMATION OF ORNITHINE CONTAINING CYCLIC BETA-CASOMORPHIN ANALOGS AND RELATED PEPTIDES

Low energy conformers of both active and nearly inactive cyclic beta-c asomorphin analogues, such as Tyr-c[-Orn-X-Pro-Gly-], Tyr-c[-Orn-X-D-P ro-Gly-], Tyr-c[-D-Orn-X-Pro-Gly-] and Tyr-c[-D-orn-X-D-Pro-Gly-] (X=P he or 2-Nal) have been determined in a systematic conformational searc h using the TRIPOS force field. The obtained conformations were compar ed with a model based on structure(conformation)-activity relationship s for mu-selective non-peptide opiates and taking into consideration b oth conformational features and molecular electrostatic potentials. On the basis of these findings we were able to propose plausible pharmac ophoric structures for the cyclic beta-casomorphins. These conformatio ns were in close agreement with those determined in solution by H-1 NM R spectroscopy. The pharmacophoric moieties contained in these structu res are in a spatial disposition which allows them to interact with se veral proposed subsites of the mu-receptor. These are an anionic site (area A) engaged in an electrostatic interaction with the protonated N -terminus of the peptides, two hydrophobic sites (areas C and D) that are both occupied by aromatic rings (Tyr and Phe in the case of the pe ptides) and two hydrophilic receptor-binding sites (areas B and F). In all peptides the N-terminal tyrosine residue assumes a very similar c onformation, permitting its interaction with receptor areas A, B and C . Furthermore, the intramolecular distance between the centroids of th e Phe(3) aromatic ring (interacting with area D) and the Tyr(1) ring i s about 10 to 11 Angstrom. According to the model, a further receptor subsite designated as F interacts with the carbonyl of the D-Orn(2) re sidue and in the case of the morphiceptin analogues with the carbonyl group of either cisPro(2) or Pro(4). The array of proposed receptor su bsites also accommodates various opiate alkaloids, several enkephalin analogues and the message domain of dermorphins and demorphins. Furthe rmore, the model provides an explanation for the lack of activity obse rved with cyclic beta-casomorphin analogues containing L-ornithine in the 2-position of the peptide sequence. The similarity between the pha rmacophore conformations of the opioid peptides and the non-peptide op iates suggests that their mode of binding to the receptor may be simil ar.