TY - JOUR
T1 - Benzyloxybenzylammonium chlorides
T2 - Simple amine salts that display anticonvulsant activity
AU - Lee, Hyosung
AU - Gold, Alexander S.
AU - Yang, Xiao Fang
AU - Khanna, Rajesh
AU - Kohn, Harold
N1 - Funding Information:
We thank Dr. Ki Duk Park for preparing several of the intermediates used in this study. We thank Weina Ju and Sarah Wilson for preparing cortical neurons. This work is supported by a grant from the North Carolina Biotechnology Center (Technology Enhancement Grant) administered by the University of North Carolina-Chapel Hill. We thank the NINDS and the ASP with Drs. Tracy Chen and Jeffrey Jiang for kindly performing the pharmacological studies via the ASP’s contract site at the University of Utah with Drs. H. Wolfe, H.S. White, and K. Wilcox. We express our appreciation to Dr. Bryan L. Roth and Mr. Jon Evans at the National Institute of Mental Health (NIMH) Psychoactive Drug Screening Project for performing in vitro receptor binding studies. This work was supported by NIMH Psychoactive Drug Screening Program, Contract No. HHSN-271-2008-00025-C (NIMH-PDSP). The NIMH PDSP is directed by Bryan Roth MD, PhD, University of North Carolina–Chapel Hill, and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. The authors are solely responsible for the content of this report, and it does not represent the official views of the National Center for Research Resources, National Institutes of Health.
PY - 2013/12/15
Y1 - 2013/12/15
N2 - Several antiepileptic drugs exert their activities by inhibiting Na + currents. Recent studies demonstrated that compounds containing a biaryl-linked motif (Ar-X-Ar′) modulate Na+ currents. We, and others, have reported that compounds with an embedded benzyloxyphenyl unit (ArOCH2Ar′, OCH2 = X) exhibit potent anticonvulsant activities. Here, we show that benzyloxybenzylammonium chlorides ( +H3NCH2C6H4OCH 2Ar′ Cl-) displayed notable activities in animal seizure models. Electrophysiological studies of 4-(2′- trifluoromethoxybenzyloxy)benzylammonium chloride (9) using embryonic cortical neurons demonstrated that 9 promoted both fast and slow inactivation of Na + channels. These findings suggest that the potent anticonvulsant activities of the earlier compounds were due, in part, to the benzyloxyphenyl motif and provide support for the use of the biaryl-linked pharmacophore in future drug design efforts.
AB - Several antiepileptic drugs exert their activities by inhibiting Na + currents. Recent studies demonstrated that compounds containing a biaryl-linked motif (Ar-X-Ar′) modulate Na+ currents. We, and others, have reported that compounds with an embedded benzyloxyphenyl unit (ArOCH2Ar′, OCH2 = X) exhibit potent anticonvulsant activities. Here, we show that benzyloxybenzylammonium chlorides ( +H3NCH2C6H4OCH 2Ar′ Cl-) displayed notable activities in animal seizure models. Electrophysiological studies of 4-(2′- trifluoromethoxybenzyloxy)benzylammonium chloride (9) using embryonic cortical neurons demonstrated that 9 promoted both fast and slow inactivation of Na + channels. These findings suggest that the potent anticonvulsant activities of the earlier compounds were due, in part, to the benzyloxyphenyl motif and provide support for the use of the biaryl-linked pharmacophore in future drug design efforts.
KW - Antiepileptic agents
KW - Benzyloxybenzylammonium chlorides
KW - Biaryl-linked motif
KW - Na current inhibition
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U2 - 10.1016/j.bmc.2013.10.031
DO - 10.1016/j.bmc.2013.10.031
M3 - Article
C2 - 24238903
AN - SCOPUS:84888437789
SN - 0968-0896
VL - 21
SP - 7655
EP - 7662
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 24
ER -