Probing the Stereochemical Requirements for Receptor Recognition of δ Opioid Agonists through Topographic Modifications in Position 1

A series of side-chain constrained tyrosine
derivatives, 2‘,6‘-dimethyl-β-methyltyrosines (TMT),
has been designed and incorporated into position 1 of the highly
selective δ opioid agonists DPDPE (Tyr-d-Pen2-Gly-Phe-d-Pen5-OH)
and deltorphin I (DELT I,
Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2).
Molecular mechanics
calculations on isolated TMT residues and nuclear magnetic resonance
(NMR) studies of the TMT1-containing peptides
in DMSO showed that each of the four stereoisomers of TMT favors one
particular rotamer of the side-chain χ1
torsional angle. Therefore, substitution of four TMT isomers for
Tyr1 allows us to perform a systematic
conformational
scan through three staggered rotamers of the aromatic side chain,
gauche (−), trans, and gauche
(+), and to explore
specific binding requirements of the receptor in relation to the side
chain conformation. The potency and selectivity
of four isomers of [TMT1]DPDPE and four isomers of
[TMT1]DELT I were evaluated by radioreceptor
binding
assays in the rat brain using μ- and δ-selective radiolabeled
ligands and by bioassays with guinea pig ileum (GPI,
μ receptor) and mouse vas deferens (MVD, δ receptor). In the
DPDPE series only one isomer,
[(2S,3R)-TMT1]DPDPE showed high potency and selectivity for the δ opioid receptors.
The favorable side-chain rotamers found
for this analogue, i.e., the trans rotamer of
TMT1 and the gauche (−) rotamer of
Phe4, were proposed as the most
probable δ receptor-binding conformations of DPDPE analogues.
Two [TMT1]DELT I isomers possessed
considerable
δ receptor potencies. The
(2S,3R)-TMT1 isomer appeared to be a
superpotent, but moderately δ-selective agonist,
while the (2S,3S)-TMT1 isomer showed the highest
selectivity for the δ receptors in this series. Surprisingly,
[(2R,3R)-TMT1]DELT I also was moderately potent at the δ
receptor. These results suggest that the δ receptor
requirements
for the linear DELT I analogues may be satisfied with two different
modes of binding of the (2S,3S)- and
(2S,3R)-TMT1 isomers. This study provides important guidance
for the design of peptide and non-peptide ligands
selective
for the δ opioid receptor.