1. In addition to the IUPAC-IUB Commission on Biochemical Nomenclature (J. Biol. Chem.1985,260, 14−42), this paper uses the following symbols and abbreviations: Bid, 1H-benzimidazole-2-yl; Boc,tert-butyloxycarbonyl; Boc−Gly−Bid, Boc−βAla−Bid, Boc−Gly−Gly−Bid, benzimidazole derivatives obtained from the carboxylic functions of Boc−Gly−OH, Boc−βAla−OH, and Boc−Gly−Gly−OH, respectively; Bzl, benzyl (CH2−Ph); DAGO, [d-Ala2,N-Me−Phe4,Gly-ol5]enkephalin; DALDA, Tyr−d-Arg−Phe−Lys−NH2; DCC,N,N‘-dicyclohexylcarbodiimide; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; Dmt, 2‘,6‘-dimethyl-l-tyrosine; DPDPE,cyclic[d-Pen2,5]enkephalin; DTLET, Tyr−d-Thr−Gly−Phe−Leu; Et2O, diethyl ether; EtPt, petroleum ether; GPI, guinea-pig ileum; HOBt, 1-hydroxybenzotriazole; HPLC, high-performance liquid chromatography;Ke, the antilog of pA2, which is determined as the negative log of the molar concentration of the antagonist necessary to double the agonist (deltorphin B) concentration; LiAlH4, lithium aluminum hydride; Me, methyl; MeOH, methanol; MVD, mouse vas deferens; NaBH3CN, sodium cyanoborohydride; NMM, 4-methylmorpholine; NTI, naltrindole; NH−tBut,tert-butylamine; OMe, methyl ester; Pe, petroleum ether; Ph, phenyl; TEA, triethylamine; TFA, trifluoroacetic acid; Tic, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; TIP(P), H−Tyr−Tic−Phe−(Phe)−OH; TLC, thin-layer chromatography; WSC, 1-ethyl-3-[(3‘-dimethyl)aminopropyl]carbodiimide hydrochloride; Z, benzyloxycarbonyl.
2. Evolution of the Dmt-Tic Pharmacophore: N-Terminal Methylated Derivatives with Extraordinary δ Opioid Antagonist Activity
3. Further Studies on the Dmt-Tic Pharmacophore: Hydrophobic Substituents at the C-Terminus Endow δ Antagonists To Manifest μ Agonism or μ Antagonism
4. Novel C-Terminus Modifications of the Dmt-Tic Motif: A New Class of Dipeptide Analogues Showing Altered Pharmacological Profiles Toward the Opioid Receptors