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. 2019 Aug 21;10(8):3682-3689.
doi: 10.1021/acschemneuro.9b00250. Epub 2019 Jul 1.

Novel Dimethyltyrosine-Tetrahydroisoquinoline Peptidomimetics with Aromatic Tetrahydroisoquinoline Substitutions Show in Vitro Kappa and Mu Opioid Receptor Agonism

Deanna Montgomery  1 , Jessica P Anand  2   3 , Nicholas W Griggs  2 , Thomas J Fernandez  2 , Joshua G Hartman  2 , Ashley A Sánchez-Santiago  2 , Irina D Pogozheva  1 , John R Traynor  2   3 , Henry I Mosberg  1   3
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Novel Dimethyltyrosine-Tetrahydroisoquinoline Peptidomimetics with Aromatic Tetrahydroisoquinoline Substitutions Show in Vitro Kappa and Mu Opioid Receptor Agonism

Deanna Montgomery et al. ACS Chem Neurosci. .

Abstract

The dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold was originally developed in the production of selective delta opioid receptor (DOR) antagonists. Installation of a 7-benzyl pendant on the tetrahydroisoquinoline core of this classic opioid scaffold introduced kappa opioid receptor (KOR) agonism. Further modification of this pendant resulted in retention of KOR agonism and the addition of mu opioid receptor (MOR) partial agonism, a bifunctional profile with potential to be used in the treatment of cocaine addiction.

Keywords: cocaine addiction; dimethyltyrosine−tetrahydroisoquinoline; multifunctional ligands; opioids; peptidomimetics; synthesis.

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Figures

Figure 1.
Figure 1.
Dimethyltyrosine - Tetrahydroisoquinoline (DMT-Tiq) scaffold with carbon numbering on the tetrahydroisoquinoline.
Figure 3.
Figure 3.
10a (cyan), 10d (yellow), and 10g (magenta) docked in the orthosteric site of the active conformation of KOR. Dashed yellow lines represent distance, labeled in angstroms. The para methyl group of 10a sterically clashes with V118 and W124 of KOR.
Scheme 1:
Scheme 1:. Synthesis of Benzyl Pendant Dmt-Tiq Analogues 4a-4d
(i) Boc2O; (ii) Benzylboronic acid pinacol ester, Pd(dppf)Cl2, K2CO3, acetone/water; (iii) HCl, 1,4-dioxane; (iv) diBoc-Dmt, PyBOP, 6Cl-HOBt, DIEA, DMF; (v) TFA, DCM
Scheme 2:
Scheme 2:. Synthesis of Substituted 7-Benzyl Pendant Dmt-Tiq Analogues 10a-10i
(i) BH3 SMe2, THF; (ii) CBr4, PPh3, DCM (iii) substituted benzyl bromide, Pd(dppf)Cl2, K2CO3, acetone/water; (iv) bis(pinacolato)diboron, Pd(dppf)Cl2, CH3CO2K, DMSO; (v) substituted aryl boronic acid, Pd(dppf)Cl2, K2CO3, 3:1 acetone:water; (vi) HCl, 1,4-dioxane; (vii) diBoc-Dmt, PyBOP, 6Cl-HOBt, DIEA, DMF; (viii) Zn, NH4Cl, acetone/water; (ix) TFA, DCM
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