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.
|Number of pages||9|
|Journal||Bioorganic and Medicinal Chemistry|
|State||Published - Jul 15 2015|
Bibliographical noteFunding 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.
© 2014 Elsevier Ltd. All rights reserved.
- Kappa opioid receptor
- Molecular constraint
- Potency enhancement
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry