THE MU-OPIOID AND DELTA-OPIOID PHARMACOPHORE CONFORMATIONS OF CYCLIC BETA-CASOMORPHIN ANALOGS INDICATE DOCKING OF THE PHE(3) RESIDUE TO DIFFERENT DOMAINS OF THE OPIOID RECEPTORS

Cyclic beta-casomorphin analogues with a D-configured amino acid resid ue in position 2, such as Tyr-o[-Xaa-Phe-Pro-Gly-] and Tyr-c[-Xaa-Phe- D-Pro-Gly-] (Xaa = D-A(2)bu, D-Orn, D-Lys) were found to bind to the m u-opioid receptor as well as to the delta-opioid receptor, whereas the corresponding L-Xaa(2) derivatives are nearly inactive at both. Low-e nergy conformers of both active and nearly inactive derivatives have b een determined in a systematic conformational search or by molecular d ynamics simulations using the TRIPOS force field. The obtained conform ations were compared with regard to a model for mu-selective opiates d eveloped by Brandt et al. [Drug Des. Discov., 10 (1993) 257]. Superpos itions as well as electrostatic, lipophilic and hydrogen bonding simil arities with the delta-opioid receptor pharmacophore conformation of t -Hpp-JOM-13 proposed by Mosberg et al. [J. Med. Chem., 37 (1994) 4371, 4384] were used to establish the probable delta-pharmacophoric cyclic beta-casomorphin conformations. These conformations were also compare d with a delta-opioid agonist (SNC 80) and the highly potent antagonis t naltrindole. These investigations led to a prediction of the mu- and beta-pharmacophore structures for the cyclic beta-casomorphins. Inter estingly, for the inactive compounds such conformations could not be d etected. The comparison between the mu- and delta-pharmacophore confor mations of the cyclic beta-casomorphins demonstrates not only differen ces in spatial orientation of both aromatic groups, but also in the ba ckbone conformations of the ring part. In particular, the differences in Phi(2) and Psi(2) (mu approximate to 70 degrees,-80 degrees; delta approximate to 165 degrees,55 degrees) cause a completely different sp atial arrangement of the cyclized peptide rings when all compounds are matched with regard to maximal spatial overlap of the tyrosine residu e. Assuming that both the mu- and delta-pharmacophore conformations bi nd with the tyrosine residue in a similar orientation at the same tran smembrane domain X of their receptors, the side chain of Phe(3) as a s econd binding site has to dock with different domains.