A new approach to receptor ligand design: synthesis and conformation of a new class of potent and highly selective μ opioid antagonists utilizing tetrahydroisoouinoline carroxylic acid

NMR studies of the structure and dynamics of peptide E, an endogenous opioid peptide that binds with high affinity to multiple opioid receptor subtypes

“…Previous restrained analogue studies have also indicated that a ␤-turn in the N-terminal domain spanning residues 3-6, such as that we have observed for adrenal peptide E, dictates high -opioid receptor specificity. 54 …”

Conformation-activity relationships of opioid peptides with selective activities at opioid receptors

“…For this purpose, we have taken several approaches (e.g., see Refs. [45][46][47][48][49][50] that mainly fall into two groups: (1) cyclization of amino acids (e.g., Tic), or (2) torsional angles constraint by suitable substitutions (␤-CH 3 or i-Pr, etc.). In the process, we have developed force fields that quite accurately predict preferred conformations and energy barriers (reviewed in Ref.…”

“…An important constrained residue we used for this purpose was 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic), which only has available the gauche(-) and gauche(ϩ) side-chain conformations. 45 It was shown (Table V) 84 with substantial increases in binding affinity for the opioid receptor and decreases in binding to the ␦ opioid receptor. The topographically constrained N-terminal D-Tic compounds all showed potent antagonist activity in GPI assays.…”

“…Interestingly, when compared to the Tic-containing compounds, replacement of the structurally constrained N-Me-D-Phe resulted in a marked decrease in binding at the opioid receptor. 45 CTOP's 20-member ring also was conformationally constrained further by substitution of (Table V). Based on conformational nmr analysis, the compounds were more flexible, and on the basis of the binding data the reduced amide bond-containing peptide analogues were less potent, with a modest decrease in selectivity of over ␦ opioid receptors.…”

Amino acid oxidase‐catalysed resolution and Pictet–Spengler reaction towards chiral and rigid unnatural amino acids

“…Among the unnatural amino acids, chiral and rigid structures have become interesting building blocks for the synthesis of specific biologically active compounds. Unnatural chiral amino acids based on the 1,2,3,4‐tetra–hydroisoquinolinecarboxylic acid skeleton can be regarded as conformationally restricted amino acid analogues of phenylalanine and tyrosine because the side chain has been fixed by the bridging methylene unit and the bicyclic nature of the molecules limits the dihedral angle in the N‐C(α)‐C(β)‐C(γ)‐ and C(α)‐C(β)‐C(γ)‐C(δ)‐segments to a small range 1…”