A uniform molecular model of δ opioid agonist and antagonist pharmacophore conformations

On the basis of a model of the pharmacophore conformations of agonist of the delta-opioid receptor the corresponding delta-antagonist conformations were determined by means of force field calculations. The results explain the unusual behavior of several cyclic beta-casomorphin analogues on the molecular level. Thus, for instance, the model helps to understand why Tyr-c[D-Orn-2-Nal-D-Pro-Gly] is a mixed mu-agonist and delta-antagonist. Furthermore, the model is consistent with low energy conformations of other delta-antagonists such as Tyr-Tic-Phe, Tyr-Tic-Phe-Phe, naltrindole and BNTX. The occupation of a special spatial area by bulky groups close to the protonated N-terminus of opioid peptides is assumed to be highly critical for the switch from agonist to antagonist behavior.