ISSN:
0006-3525
Keywords:
Chemistry
;
Polymer and Materials Science
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
In order to study structure-activity relationships of enkephalin-related analogues, we report the biological activity and conformational analysis of four 14-membered cyclic enkephalin analogues with β-(1-naphthyl)alanine in place of phenylalanine at the fourth position, Tyr-c[D-A2bu-Gly-(L and D)-βNal(1)-(L and D)-Leu]. The L-βNal(1)-containing analogues display higher activity at both the μ and δ receptors than the corresponding analogues with the L-Phe residue. In contrast to the linear enkephalins, the cyclic analogues with the D-βNal(1) residue are also active at the μ receptor since the relative spatial arrangement of functional groups required for biological activity is achieved by the constrained nature of the cyclic molecules. A comparison of the findings from the conformational analysis and biological assays establishes that relatively extended structures, in which the two aromatic side chains are oriented in opposite directions with a ∼ 14Å separation, is required for activity at the μ receptor. On the other hand, folded conformations with nearly parallel orientations and a close proximity ( 〈 10Å) of the aromatic rings of the Tyr and βNal(1) residues are required for activity at the δ receptor. It should be noted that the overall structures and thus the biological profiles of the 14-membered cyclic enkephalin analogues are strongly dependent on the conformation of the second residue. The folded conformations with parallel orientation of the two aromatic side chains of Tyr-c [D-A2bu-Gly-L-βNal (1)-D-Leu] is stabilized by an interaction between the Tyr phenolic OH proton and βNal(1) C*O groups. This analogue, which shows the highest activity at both the μ and δ receptors among the four stereoisomers studied, displays an increase of the fraction of the side-chain χ1 = t conformer for the βNal(1) residue. It is concluded that the incorporation of the D-Leu residue at the fifth position increases the relative fraction of the folded conformations with parallel orientation of the aromatic side chains, and hence enhances activity at the δ receptor as compared to the corresponding L-Leu containing analogue.
Additional Material:
11 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/bip.360310708
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