ISSN:
1438-2199
Keywords:
Amino Acids
;
Deltorphins
;
Peptide synthesis
;
Opioid receptors
;
Molecular dynamics simulations
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary Analysis of deltorphin A position 4 analogues included: backbone constrained N α MeHis, spinacine (Spi), N α MePhe and the tetrahydroisoquinoline-3-carboxylic acid (Tic); spatially confined side-chain (Phg); and imidazole alkylation ofl- andd-His4 enantiomers. Highδ selectivity was lost with the following replacements: N α MeHis4, N α MePhe4 and Phg4 reducedδ binding and the constrained residues also increasedµ binding; ring closure between the side-chain and amino group to yield Spi4 or Tic4 increasedµ affinity. Imidazole methylation of His4 marginally affected opioid binding and doubledδ selectivity; alkylatedd-His4-derivatives generally maintainedδ selectivity in spite of decreasedδ affinities. Thus, His4 imidazole preservesδ selectivity by facilitating highδ binding and by repulsion at theµ receptor. Several low energy conformers of deltorphin A indicated that the His4 imidazole preferred a spatial orientation parallel to the phenolic side-chain of Tyr1 suggestive that this conformation might contribute to highδ affinity and selectivity.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00807704
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