We have proposed that development of methods for controlling the side-chain topography of amino acid residues in peptides and proteins provides a new approach to the topographical design of biologically active peptides. An example of this approach is the use of the 1,2,3,4-tetrahydroisoquinolinecarboxylic acid (Tic) residue, which favors a gauche (-) side-chain conformation when in the N-terminal position, whereas in its acylated form (internal position), the most stable side-chain conformation is gauche (+). This approach has been tested by incorporating D-Tic or Tic at different positions of μ opioid receptor specific octapeptides such as D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP, 1), examination of the biological consequences of these modifications, and detailed NMR based conformational analysis. The compounds prepared and their biological activities were as follows: D-Tic-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (2; gauche (-), /μ = 7800, IC50 μ = 1.2 nM); Gly-D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (3; gauche (+), /μ = 19, IC50 μ = 278.7 nM); and D-Phe- Cys-Tic-D-Trp-Orn-Thr-Pen-Thr-NH2 (4; gauche (+), /μ = ~7, IC50 μ = 1439.0 nM). In the absence of a geminal pair of protons suitable for distance calibration, a new technique (Davis, D. G. J. Am. Chem. Soc. 1987,109, 3471–3472) of transverse and longitudinal cross-relaxation rate measurements has been utilized in conjunction with other 2D NMR methods in order to determine the three-dimensional solution conformations for the peptides 1–4, with subsequent application of restrained molecular dynamics (gromos). The average backbone conformations in peptides 1–4 were very similar, but the side-chain conformational preferences in the analogues differed, suggesting that the different affinities and selectivities for μ opioid receptors were primarily due to differences in the side-chain conformations of Tic (d-T1c), and thus due to differences in the topographies of these peptides, and not the backbone conformations. A detailed analysis of these relationships is presented.
ASJC Scopus subject areas
- Colloid and Surface Chemistry