The μ-and δ-opioid pharmacophore conformations of cyclic β-casomorphin analogues indicate docking of the Phe³ residue to different domains of the opioid receptors

Summary

Cyclic β-casomorphin analogues with a d-configured amino acid residue in position 2, such as Tyr-c[-Xaa-Phe-Pro-Gly-] and Tyr-c[-Xaa-Phe-d-Pro-Gly-] (Xaa=d-A₂bu, d-Orn, d-Lys) were found to bind to the μ-opioid receptor as well as to the δ-opioid receptor, whereas the corresponding l-Xaa² derivatives are nearly inactive at both. Low-energy conformers of both active and nearly inactive derivatives have been determined in a systematic conformational search or by molecular dynamics simulations using the TRIPOS force field. The obatained conformations were compared with regard to a model for μ-selective opiates developed by Brandt et al. [Drug Des. Discov., 10 (1993) 257]. Superpositions as well as electrostatic, lipophilic and hydrogen bonding similarities with the δ-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 δ-pharmacophoric cyclic β-casomorphin conformations. These conformations were also compared with a δ-opioid agonist (SNC 80) and the highly potent antagonist naltrindole. These investigations led to a prediction of the μ-and δ-pharmacophore structures for the cyclic β-casomorphins. Interestingly, for the inactive compounds such conformations could not be detected. The comparison between the μ-and δ-pharmacophore conformations of the cyclic β-casomorphins demonstrates not only differences in spatial orientation of both aromatic groups, but also in the backbone conformations of the ring part. In particular, the differences in Φ² and Ψ² (μ≈70°,-80°; δ≈165°,55°) cause a completely different spatial arrangement of the cyclized peptide rings when all compounds are matched with regard to maximal spatial overlap of the tyrosine residue. Assuming that both the μ-and δ-pharmacophore conformations bind with the tyrosine residue in a similar orientation at the same transmembrane domain X of their receptors, the side chain of Phe³ as a second binding site has to dock with different domains.