1. The receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH-related delta-opioid antagonists contains all trans peptide bonds
B C Wilkes, T M Nguyen, G Weltrowska, K A Carpenter, C Lemieux, N N Chung, P W Schiller J Pept Res. 1998 May;51(5):386-94. doi: 10.1111/j.1399-3011.1998.tb01229.x.
Two different models for the receptor-bound conformation of delta-opioid peptide antagonists containing the N-terminal dipeptide segment H-Tyr-Tic (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) have been proposed. Both models are based on spatial overlap of the Tyr1 and Tic2 aromatic rings and N-terminal amino group with the corresponding aromatic rings and nitrogen atom of the nonpeptide delta-antagonist naltrindole. However, in one model the peptide bond between the Tyr1 and Tic2 residues assumes the trans conformation, whereas in the other it is in the cis conformation. To distinguish between these two models, we prepared the two peptides H-Tyr(psi)[CH2NH]Tic-Phe-Phe-OH and H-Tyr(psi)[CH2NH]MeTic-Phe-Phe-OH (MeTic = 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) in which a cis peptide bond between the Tyr and Tic (or MeTic) residues is sterically forbidden. Both compounds turned out to be moderately potent delta-opioid antagonists in the mouse vas deferens assay. A molecular mechanics study performed with both peptides resulted in low-energy conformations in which the torsional angle ("omega1") of the reduced peptide bond between Tyr and Tic (or MeTic) had a value of 180 degrees (trans conformation) and which were in good agreement with the proposed model with all trans peptide bonds. Furthermore, this study confirmed that neither of these two peptides could assume low-energy conformations in which "omega1" had a value of 0 degrees (cis conformation). Conformers with that same bond in the gauche conformation ("omega1" = -60 degrees) were also identified, but were higher in energy and showed no spatial overlap with naltrindole. On the basis of these results it is concluded that the receptor-bound conformation of delta-peptide antagonists containing an N-terminal H-Tyr-Tic-dipeptide segment must have all trans peptide bonds.
2. Novel TIPP (H-Tyr-Tic-Phe-Phe-OH) analogues displaying a wide range of efficacies at the δ opioid receptor. Discovery of two highly potent and selective δ opioid agonists
Irena Berezowska, Carole Lemieux, Nga N Chung, Jinguo Ding, Peter W Schiller Bioorg Med Chem Lett. 2012 Mar 1;22(5):1899-902. doi: 10.1016/j.bmcl.2012.01.063. Epub 2012 Jan 28.
Analogues of the δ opioid antagonist peptide TIPP (H-Tyr-Tic-Phe-Phe-OH; Tic=1,2,3,4-tetrahydroisoquinoline3-carboxylic acid) containing various 4'-[N-(alkyl or aralkyl)carboxamido]phenylalanine analogues in place of Tyr(1) were synthesized. The compounds showed subnanomolar or low nanomolar δ opioid receptor binding affinity and various efficacy at the δ receptor (antagonism, partial agonism, full agonism) in the [(35)S]GTPγS binding assay. Two analogues, [1-Ncp(1)]TIPP (1-Ncp=4'-[N-(2-(naphthalene-1-yl)ethyl)carboxamido]phenylalanine) and [2-Ncp(1)]TIPP (2-Ncp=4'-[N-(2-(naphthalene-2-yl)ethyl)carboxamido]phenylalanine), were identified as potent and selective δ opioid agonists.
3. Comparative analysis of various proposed models of the receptor-bound conformation of H-Tyr-Tic-Phe-OH related delta-opioid antagonists
B C Wilkes, P W Schiller Biopolymers. 1995;37(6):391-400. doi: 10.1002/bip.360370606.
A molecular mechanics study (grid search and energy minimization) was performed with six delta opioid peptide antagonists containing a tetrahydroisoquinoline-3-carboxylic acid (Tic) residue in the 2-position of the peptide sequence. Compounds examined were the highly potent and selective TIP(P) peptides H-Tyr-Tic-Phe-OH (TIP), H-Tyr-Tic psi[CH2-NH]Phe-OH (TIP[psi]), H-Tyr-Tic-Phe-Phe-OH (TIPP), and H-Tyr-Tic psi[CH2-NH]Phe-Phe-OH (TIPP[psi]), and the weakly active analogues H-Tyr-Tic-NH2 and H-Tyr-Tic-Ala-OH. Low energy conformers of the peptides were examined for their compatibility with three proposed models of the delta receptor-bound conformation. Model 1, based on spatial overlap of the Tyr1 and Phe3 aromatic rings and N-terminal amino group of the peptides with the corresponding aromatic rings and nitrogen atom of the nonpeptide delta-antagonist naltrindole, was ruled out because of the demonstrated importance of the Tic2 aromatic ring for delta antagonism and because of the somewhat elevated energies of the conformers consistent with this model. Models of the receptor-bound conformation based on superimposition of the Tyr1 and Tic2 aromatic rings and N-terminal amino group of the peptides with the corresponding moieties in naltrindole included an all-trans peptide bond conformer [model 2, proposed by B.C. Wilkes and P.W. Schiller (1994) Biopolymers, Vol. 34, pp. 1213-1219] and a conformer with a cis peptide bond between the Tyr1 and Tic2 residues (model 3, originally proposed by P.A. Temussi et al. [(1994) Biochemical and Biophysical Research Communications, Vol. 198, pp. 933-939]. For all six peptides low energy conformers consistent with both model 2 and model 3 were identified; however, peptide conformers corresponding to model 2 showed better coplanarity of the Tyr1 aromatic ring and the phenol ring in naltrindole than peptide conformers corresponding to model 3. Both models remain plausible candidate structures for the receptor-bound conformation of delta antagonists of the TIP(P) class. TIP(P) analogues containing additional conformational constraints need to be developed in order to arrive at a unique model.
