Three-dimensional structure for the beta 2 adrenergic receptor protein based on computer modeling studies.

Computer-aided model building techniques have been used to construct three-dimensional model structures for hamster beta 2 adrenergic receptor. Experimental data were used as constraints to guide the model building procedure, and a number of rather strict criteria were applied to assess the physical plausibility of model structures. We present details of our best model structure to date, which is consistent with a large body of experimental data. We also discuss in detail our model building procedures and evaluation criteria, which we believe may be of general utility in modeling projects.

Role of spacer and address components in peptidomimetic delta opioid receptor antagonists related to naltrindole.

A series of heterocyclic analogues 2-5 related to naltrindole (1) (NTI) and 6-arylnaltrexone derivatives 6-8 were synthesized in order to determine the role of the spacer and the address moieties in conferring delta opioid receptor antagonist activity. The benzofuran (NTB), quinoxaline, and quinoline analogues (2, 3, and 4, respectively) were delta-selective opioid antagonists in vitro and bound selectively to delta receptors. The tetrahydroindole derivative 5, while delta-selective, was considerably less potent than its indole analogue 13. The data for 2-4 indicate that heterocycles other than pyrrole can serve as a spacer for the delta address moiety. Moreover, the lower delta antagonist potency of 5 illustrates the importance of the aromatic address component. Molecular dynamics simulations of enkephalin using a zipper binding model are consistent with a delta address subsite that may accommodate the benzene moiety of NTI or the Phe4 phenyl group of leucine enkephalin. The considerably lower delta opioid receptor antagonist potencies of the 6-aryl derivatives 6-8 are consistent with the conformational mobility of the aryl group and its location in the molecule.