The mu- and delta-opioid pharmacophore conformations of cyclic beta-casomorphin analogues indicate docking of the Phe3 residue to different domains of the opioid receptors.
Cyclic beta-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 mu-opioid receptor as well as to the delta-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 obtained conformations were compared with regard to a model for mu-selective opiates developed by Brandt et al. [Drug Des. Discov., 10 (1993) 257]. Superpositions as well as electrostatic, lipophilic and hydrogen bounding similarities 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 compared with a delta-opioid agonist (SNC 80) and the highly potent antagonist naltrindole. These investigations led to a prediction of the mu- and delta-pharmacophore structures for the cyclic beta-casomorphins. Interestingly, for the inactive compounds such conformations could not be detected. The comparison between the mu- and delta-pharmacophore conformations of the cyclic beta-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 on phi2 and psi2 (mu approximately 70 degrees, -80 degrees; delta approximately 165 degrees, 55 degrees) 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 mu- and delta-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.
Brandt
W
W
Institute of Biochemistry, Martin-Luther-University Halle-Wittenberg, Germany.
Stoldt
M
M
Schinke
H
H
D003196:Computer Graphics; D003198:Computer Simulation; D004723:Endorphins / Q000737:chemistry*; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017465:Receptors, Opioid, delta / Q000737:chemistry*; D017450:Receptors, Opioid, mu / Q000737:chemistry*
D004723:Endorphins; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D010649:Phenylalanine; C021968:beta-casomorphins