Rational design and synthesis of ligands that act with high affinity at both mu- & delta-opioid receptors

Authors

• PW DeMatteo
• YS Lee
• AR Jacobson
• KC Rice

Abstract

Two compounds with nanomolar activity for mu- and elta-opioid receptors have been synthesized. The twelve-compound library from which they were discovered demonstrates structure-activity trends, which can be further applied in the rational design of other mu-delta opioid-targeting compounds. Many of the other compounds in the library have high affinity at the mu- and a few at the mu-, delta-, and kappa-opioid receptors. DFT calculations implicate a novel interaction with a residue within the opioid binding pocket that could be targeted in the design of high affinity and selective mu-delta ligands. Such compounds have been noted to have fewer side-effects than the morphine-like mu selective ligands.

Scientific Focus Area: Molecular Pharmacology

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