posted on 2003-08-16, 00:00authored byBalvinder S. Vig, Mike Q. Zheng, Thomas F. Murray, Jane V. Aldrich
Phenylalanine at position 4 of the peptide dynorphin A (Dyn A) is an important residue for
opioid receptor affinity and activity, but there is very little information available on the
structure−activity relationships or conformational preference of this residue for interaction
with κ-opioid receptors. Based on the hypothesis that the spatial orientation of the aromatic
ring at position 4 of Dyn A is important for opioid receptor affinity and selectivity, a series of
Dyn A analogues with various Phe derivatives substituted at position 4 were synthesized and
evaluated for their opioid receptor affinity and activity. The l- and d-Homophe4 (homophenylalanine) analogues of [d-Ala8]Dyn A-(1−11)NH2 were compared to the (R)- and (S)-Atc4 (2-aminotetralin-2-carboxylic acid) derivatives (Aldrich et al. Chirality 2001, 13, 125−129).
[l-Homophe4,d-Ala8]Dyn A-(1−11)NH2 exhibited higher κ-opioid receptor affinity than the
d-Homophe4 isomer, while [(R)-Atc4,d-Ala8]Dyn A-(1−11)NH2 exhibited higher κ-opioid receptor
affinity than the (S)-Atc4 isomer. Comparing the structure of Atc to those of Phe and Homophe,
these results suggest that the Atc isomers are functioning more as constrained Homophe rather
than Phe analogues in these Dyn A derivatives. The higher κ-opioid receptor affinity of the
(R)-Atc4 analogue suggests that Phe4 of Dyn A most likely adopts a gauche (−) or trans
conformation in the κ-opioid receptor binding site. Comparison of [d-Ala8]Dyn A-(1−11)NH2
derivatives containing Aic4 (2-aminoindan-2-carboxylic acid) and Tic4 (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) with the peptides containing their acyclic counterparts α-MePhe4
and N-MePhe4, respectively, suggest that the loss in opioid receptor affinity seen for the Aic4
and Tic4 analogues is probably due to an improper orientation of the aromatic ring in these
residues. Most of the analogues in this series showed much lower affinity for δ-opioid receptors
than the parent peptide, suggesting that κ- and δ-opioid receptors have distinct binding pockets
for the residue at position 4 of Dyn A. All of the analogues with high affinity for κ-opioid
receptors exhibited full agonist activity in the adenylyl cyclase assay using cloned κ-opioid
receptors, indicating that changes in the position or orientation of the phenyl ring in this residue
did not alter the ability of the peptides to activate the receptor.