Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif

Kevin J. Frankowski; Stephen R. Slauson; Kimberly M. Lovell; Angela M. Phillips; John M. Streicher; Lei Zhou; David A. Whipple; Frank J. Schoenen; Thomas E. Prisinzano; Laura M. Bohn; Jeffrey Aubé

doi:10.1016/j.bmc.2014.12.033

Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif

Kevin J. Frankowski, Stephen R. Slauson, Kimberly M. Lovell, Angela M. Phillips, John M. Streicher, Lei Zhou, David A. Whipple, Frank J. Schoenen, Thomas E. Prisinzano, Laura M. Bohn, Jeffrey Aubé

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.

Original language	English
Pages (from-to)	3948-3956
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	14
DOIs	https://doi.org/10.1016/j.bmc.2014.12.033
State	Published - Jul 15 2015

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.

Keywords

Antagonist
Kappa opioid receptor
Molecular constraint
Potency enhancement
Tetrahydroisoquinoline

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Frankowski, K. J., Slauson, S. R., Lovell, K. M., Phillips, A. M., Streicher, J. M., Zhou, L., Whipple, D. A., Schoenen, F. J., Prisinzano, T. E., Bohn, L. M., & Aubé, J. (2015). Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif. Bioorganic and Medicinal Chemistry, 23(14), 3948-3956. https://doi.org/10.1016/j.bmc.2014.12.033

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abstract = "Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.",

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Frankowski, KJ, Slauson, SR, Lovell, KM, Phillips, AM, Streicher, JM, Zhou, L, Whipple, DA, Schoenen, FJ, Prisinzano, TE, Bohn, LM & Aubé, J 2015, 'Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif', Bioorganic and Medicinal Chemistry, vol. 23, no. 14, pp. 3948-3956. https://doi.org/10.1016/j.bmc.2014.12.033

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T1 - Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif

AU - Frankowski, Kevin J.

AU - Slauson, Stephen R.

AU - Lovell, Kimberly M.

AU - Phillips, Angela M.

AU - Streicher, John M.

AU - Zhou, Lei

AU - Whipple, David A.

AU - Schoenen, Frank J.

AU - Prisinzano, Thomas E.

AU - Bohn, Laura M.

AU - Aubé, Jeffrey

PY - 2015/7/15

Y1 - 2015/7/15

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AB - Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.

KW - Antagonist

KW - Kappa opioid receptor

KW - Molecular constraint

KW - Potency enhancement

KW - Tetrahydroisoquinoline

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EP - 3956

JO - Bioorganic and Medicinal Chemistry

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ER -

Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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