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

Funding Information:
We gratefully acknowledge financial support from the National Institute on Drug Abuse (Grant R01 DA031927 to L.M.B. and J.A.). We thank Ben Neuenswander for performing HPLC compound purification and high resolution mass determinations. K i determinations were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program , Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and project officer Jamie Driscoll at NIMH, Bethesda MD, USA.

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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10.1016/j.bmc.2014.12.033

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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.",

keywords = "Antagonist, Kappa opioid receptor, Molecular constraint, Potency enhancement, Tetrahydroisoquinoline",

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note = "Funding Information: We gratefully acknowledge financial support from the National Institute on Drug Abuse (Grant R01 DA031927 to L.M.B. and J.A.). We thank Ben Neuenswander for performing HPLC compound purification and high resolution mass determinations. K i determinations were generously provided by the National Institute of Mental Health{\textquoteright}s Psychoactive Drug Screening Program , Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and project officer Jamie Driscoll at NIMH, Bethesda MD, USA. Publisher Copyright: {\textcopyright} 2014 Elsevier Ltd. All rights reserved.",

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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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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

N1 - Funding Information: We gratefully acknowledge financial support from the National Institute on Drug Abuse (Grant R01 DA031927 to L.M.B. and J.A.). We thank Ben Neuenswander for performing HPLC compound purification and high resolution mass determinations. K i determinations were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program , Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and project officer Jamie Driscoll at NIMH, Bethesda MD, USA. Publisher Copyright: © 2014 Elsevier Ltd. All rights reserved.

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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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