Dmt and opioid peptides: A potent alliance

Abstract

The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance.

Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

“…Pseudopeptides (1)(2)(3)(4)(5)(6) were prepared in solution by peptide synthetic methods. Simply, BocDmt-Tic-OH 19 was coupled with H 2 N-CH 2 -hetero-/homo-cycle via WSC/HOBt.…”

“…Simply, BocDmt-Tic-OH 19 was coupled with H 2 N-CH 2 -hetero-/homo-cycle via WSC/HOBt. Final Nterminal Boc deprotection with TFA and purification by preparative HPLC, gave compounds (1)(2)(3)(4)(5)(6). The intermediates (benzo [d]oxazol-2-yl)methanamine (H 2 N-CH 2 -Boa) and (benzo [d] thiazol-2-yl)methanamine (H 2 N-CH 2 -Bta) were prepared according to the procedure of Nestor et al 13 Mixed carbonic anhydride coupling of Z-Gly-OH with o-aminophenol gave the crude intermediate amide, which was converted without purification to the desired benzoxazole (Z-NH-CH 2 -Boa) by cyclization and dehydration in refluxing propionic acid (~140°C).…”

“…After solvent evaporation, the residue was purified by column chromatography as reported above. For Z-NH-CH 2 tert-butyl (4-phenyl-1H-imidazol-2-yl)methylcarbamate (Boc-NH-CH 2 -ImidPh)-A solution of Boc-Gly-OH (2.87 g, 16.4 mmol) and cesium carbonate (2.7 g, 8.3 mmol) in EtOH (50 mL) was shaken for 30 min at room temperature, and then evaporated under reduced pressure. To the resulting salt in DMF (60 mL) was added 2-bromoacetophenone (3.26 g, 16.4 mmol).…”

“…The IC 50 values represent the mean ± SE of five or six separate assays. δ -antagonist potencies in the MVD assay were determined against the δ -agonist DPDPE; μ-antagonism in the GPI assay used the μ-agonist PL-017 and both are expressed as pA 2 Structures of new compounds 1-6. Table 1 Receptor Binding Affinities and Functional Bioactivities of Compounds 1-6.…”

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

“…It was well known that the replacement of tyrosine with Dmt dramatically increases the opioid activities in most cases. 22 Ligand 10, where the Phe (p-Cl) residue was replaced by the Dmt, showed increased binding at the d and l opioid receptors compared to ligand 6, but there were no differences in functional assays. It is likely that ligands 3-4 and 6-10 do not have the appropriate topography to activate the opioid receptors but their low micromolar range of binding affinities at these receptors might be attributed to the C-terminal moiety, N-phenyl-N-piperidin-4-yl-propionamide.…”