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

Producción científica: Article › revisión exhaustiva

8 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	3948-3956
Número de páginas	9
Publicación	Bioorganic and Medicinal Chemistry
Volumen	23
N.º	14
DOI	https://doi.org/10.1016/j.bmc.2014.12.033
Estado	Published - jul 15 2015

Nota bibliográfica

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

Financiación

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.

Financiadores	Número del financiador
National Institute on Drug Abuse
National Institute of Mental Health	HHSN-271-2013-00017-C
National Institute on Drug Abuse	R01DA031927

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

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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doi = "10.1016/j.bmc.2014.12.033",

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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, n.º 14, pp. 3948-3956. https://doi.org/10.1016/j.bmc.2014.12.033

TY - JOUR

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

N2 - 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.

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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DO - 10.1016/j.bmc.2014.12.033

M3 - Article

C2 - 25593096

AN - SCOPUS:84930863998

SN - 0968-0896

VL - 23

SP - 3948

EP - 3956

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 14

ER -

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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