The stereochemical requirements of the novel δ-opioid selective dipeptide antagonist TMT-Tic

doi:10.1016/S0960-894X(97)10145-7

Bioorganic & Medicinal Chemistry Letters

Volume 7, Issue 23, 2 December 1997, Pages 3049-3052

https://doi.org/10.1016/S0960-894X(97)10145-7 Get rights and content

Abstract

Five conformationally constrained dipeptide TMT-L-Tic analogues have been synthesized and evaluated for their bioactivity using in vitro bioassays. The most potent and selective analogue (2S,3R)-TMT-L-Tic showed 9 nM binding affinity and 4000-fold selectivity for the δ vs μ opioid receptor. The lowest-energy conformation of (2S,3R)-TMT-L-Tic is suggested to be bioactive one in which the χ₁ torsional angle is trans for TMT and gauche (+) for Tic.

Five conformationally constrained dipeptide TMT-L-Tic analogues have been synthesized and evaluated using in vitro bioassays

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Citation Excerpt :
The receptor was purified by metal chelating and ligand affinity chromatography and characterized as published previously (6, 8). For the studies in which the receptor was pre-bound with ligand, the hDOR was preincubated with saturating amounts (at least 1 order of magnitude higher concentration than published binding affinities) of ligand, using two peptide agonists, DPDPE (American Peptide Co.) and deltorphin II (prepared in our laboratory by standard methods of solid phase peptide synthesis (9)), two non-peptide agonists, SNC80 (Tocris Inc., Elisville, MO) and (–)-Tan67 (Toray Industries, Kumakura, Japan), a partial agonist, morphine (Sigma), an antagonist, NTI (Sigma), and an inverse agonist, TMT-L-Tic (synthesized in Dr. Hruby's laboratory following published procedures (10)). The receptor was incubated with the respective ligand for 1–2 h at 4 °C prior to incorporation into the PWR cell that contained a previously deposited lipid bilayer on the resonator surface.
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^†: Permanent address: Department of Chemistry, Yunnan University, Kunming, P.R. China

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The stereochemical requirements of the novel δ-opioid selective dipeptide antagonist TMT-Tic

Abstract

Biochem. Biophys. Res. Commun.

Tetrahedron

Tetrahedron Lett.

Life Sci.

Biochem. Biophys. Res. Comm.

Tetrahedron

FEBS Lett.

J. Med. Chem.