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Enkephalin analogues containing β‐naphthylalanine at the fourth position
Author(s) -
Mierke Dale F.,
SaidNejad Odile E.,
Schiller Peter W.,
Goodman Murray
Publication year - 1990
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360290123
Subject(s) - chemistry , stereochemistry , side chain , enkephalin , phenylalanine , tyrosine , ring (chemistry) , dipeptide , intramolecular force , residue (chemistry) , hydrogen bond , peptide , receptor , amino acid , molecule , biochemistry , opioid , organic chemistry , polymer
To examine the importance of the aromatic side chains of enkephalin on opiate activity, we report the synthesis and conformational analysis of a series of analogues related to enkephalin with β‐naphthylalanine in place of phenylalanine at the fourth position. Three linear analogues (Tyr‐ D ‐Ala‐Gly‐( L and D )‐β Nal(1)‐Leu‐NH 2 and Tyr‐ D ‐Ala‐Gly‐β Nal(2)‐Leu‐NH 2 ) were initially synthesized to examine the effect of the substitution on biological activity. The increased activity of these peptides at the μ‐opiate receptor, compared to native Leu‐enkephalin, prompted us to examine the more conformational constrained analogues, Tr‐c[ D ‐A 2 bu‐Gly‐( L and D )‐β Nal(1)‐Leu], incorporating a α,γ‐diaminobutyric acid at the second position and cyclization to the carboxylic end of the leucine. These two cyclic analogues provide insight into the necessity for the L chirality of the aromatic residue at position 4. The Tyr‐c[ D ‐A 2 bu‐Gly‐ L ‐β Nal(1)‐Leu] analogue is highly potent and displays a slight preference for the μ receptor. The conformational analysis indicates that despite the high flexibility of the tyrosine side chain, the aromatic rings of the tyrosine and naphthylalanine are relatively distant from each other. The presence of two intramolecular hydrogen bonds help maintain the conformation of the 14‐membered backbone ring that keeps the side chains directed away from each other. These findings are in agreement with our model of an extended structure required for μ selectivity and a folded form with close aromatic ring placement for δ selectivity.