Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jun 13;56(11):4551-67.
doi: 10.1021/jm400275h. Epub 2013 May 16.

Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists

Chad M Kormos  1 , Chunyang Jin, Juan Pablo Cueva, Scott P Runyon, James B Thomas, Lawrence E Brieaddy, S Wayne Mascarella, Hernán A Navarro, Brian P Gilmour, F Ivy Carroll
Affiliations

Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists

Chad M Kormos et al. J Med Chem. .

Abstract

There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [(35)S]GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [(35)S]GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [(35)S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Compound 10a (CPK color scheme) docked into the kappa-opioid receptor ligand binding site (PDB: 4DJH). The observed configuration of JDTic (yellow) shown for comparison. Electrostatic interactions indicated by yellow (hydrogen-bonds involving water) or orange (interactions with Asp 238) dashed lines.
Figure 2
Figure 2
Compound 11e (CPK color scheme) docked into the kappa-opioid receptor ligand binding site (PDB: 4DJH). The observed configuration of JDTic (yellow) shown for comparison. Electrostatic interactions indicated by yellow (hydrogen-bonds involving water) or orange (interaction with Asp 238) dashed lines.
Scheme 1.<sup>a</sup>
Scheme 1.a
Synthesis of 10a aReagents: (a) N-Boc-L-valine, BOP, Et3N, THF; (b) BH3•THF, THF; (c) conc. HCl; (d) Boc-D-7-hydroxy-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, BOP, THF, 0 °C; (e) CF3CO2H, CH2Cl2; (f) HBTU, RCO2H, CH3CN, Et3N.
Scheme 2.<sup>a</sup>
Scheme 2.a
Synthesis of 10b aReagents: (a) 1 N HCl, THF; (b) N-Boc-L-valine, BOP, Et3N, THF; (c) BH3•S(CH3)2, THF; (d) 6 N HCl; (e) 48% HBr; (f) Boc- D-7-hydroxytetrahydroquinoline-3-carboxylic acid, BOP, Et3N, THF.
Scheme 3<sup>a</sup>
Scheme 3a
a Reagents and conditions: (a) ArCO2H, HBTU, Et3N, CH3CN.
Scheme 4<sup>a</sup>
Scheme 4a
a Reagents and conditions: (a) KOH, DMF, 175 °C, 20 min; (b) CrO3, aq. H2SO4, acetone; (c) aq. KOH, reflux; (d) HBr, AcOH, reflux; (e) HBTU, NEt3, CH3CN; (f) 16, BOP, NEt3, CH2Cl2; (g) 16, EDC•HCl, cat. HOBt, NEt3, CH2Cl2.
Scheme 5<sup>a</sup>
Scheme 5a
a Reagents and conditions: (a) KOH, DMF, 175 °C, 20 min; (b) CrO3, aq. H2SO4, acetone; (c) aq. KOH, reflux; (d) HBr, AcOH, reflux; (e) conc. HCl, THF/iPrOH; (f) 16, EDC•HCl, cat. HOBt, NEt3, CH2Cl2.
Scheme 6<sup>a</sup>
Scheme 6a
a Reagents and conditions: (a) bis(pinacolato)diborane, Pd(dppf)Cl2, KOAc; (b) Oxone, aq. acetone.
Scheme 7<sup>a</sup>
Scheme 7a
a Reagents and conditions: (a) mCPBA, DCM; (b) Ac2O, AcOH, 150 °C, 5 min; (c) aq. K2CO3, MeOH; (d) KMnO4, acetone; (e) 16, HBTU, NEt3, CH3CN.
Scheme 8<sup>a</sup>
Scheme 8a
a Reagents and conditions: (a) TMSCHN2, tol., MeOH; (b) Cs2CO3, PhOH, CH3CN, reflux; (c) aq. LiOH, MeOH; (d) 16, EDC•HCl, cat. HOBt, NEt3, CH2Cl2.
Chart 1
Chart 1
Chart 2
Chart 2
Chart 3
Chart 3
See this image and copyright information in PMC

References

    1. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev. 1996;48:567–592. - PubMed
    1. Aldrich JV, Vigil-Cruz SC. Narcotic Analgesics. In: Abraham DJ, editor. Burger’s Medicinal Chemistry and Drug Discovery. 6. Vol. 6. John Wiley & Sons; New York, NY: 2003. pp. 329–481. Chapter 7.
    1. Kreek MJ, LaForge KS, Butelman E. Pharmacotherapy of addictions. Nat Rev Drug Discov. 2002;1:710–726. - PubMed
    1. Zimmerman DM, Nickander R, Horng JS, Wong DT. New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series. Nature. 1978;275:332–334. - PubMed
    1. Thomas JB, Mascarella SW, Rothman RB, Partilla JS, Xu H, McCullough KB, Dersch CM, Cantrell BE, Zimmerman DM, Carroll FI. Investigation of the N-substituent conformation governing potency and mu receptor subtype-selectivity in (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists. J Med Chem. 1998;41:1980–1990. - PubMed

Publication types

MeSH terms

Substances