TY - JOUR
T1 - N-Substituted-3-alkoxy-derivatives of dextromethorphan are functional NMDA receptor antagonists in vivo
T2 - Evidence from an NMDA-induced seizure model in rats
AU - Witkin, Jeffrey M.
AU - Cerne, Rok
AU - Newman, Amy H.
AU - Izenwasser, Sari
AU - Smith, Jodi L.
AU - Tortella, Frank C.
N1 - Funding Information:
Primary support for this work is gratefully acknowledged from the NIDA Intramural Research Program, Baltimore, Maryland and from the Walter Reed Army Institute of Research , Washington, DC. We are also grateful to John and Nancy Peterson for their support of this research. We also thank the National Institutes of Health for support from [ MH-096463 ] and [ NS-076517 ] and The National Science Foundation , Division of Chemistry [ CHE-1625735 ]. We also acknowledge UW-Milwaukee's Shimadzu Laboratory for Advanced and Applied Analytical Chemistry and support from the Milwaukee Institute of Drug Discovery and the University of Wisconsin-Milwaukee Research Foundation.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/4
Y1 - 2021/4
N2 - Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([3H]-TCP binding) (r = 0.71, p < 0.05) but not to σ1 receptors ([3H]-SKF 10047 binding) (r = −0.31, p = 0.46) or to σ2 receptors ([3H]-DTG binding) (p = −0.38, p = 0.36). This is the first report demonstrating that these dextromethorphan analogs are functional NMDA receptor antagonists in vivo. Given their potential therapeutic utility and favorable side-effect profiles, such low affinity NMDA receptor antagonists could be considered for further development in neurological (e.g., anticonvulsant) and psychiatric (e.g., antidepressant) disorders.
AB - Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([3H]-TCP binding) (r = 0.71, p < 0.05) but not to σ1 receptors ([3H]-SKF 10047 binding) (r = −0.31, p = 0.46) or to σ2 receptors ([3H]-DTG binding) (p = −0.38, p = 0.36). This is the first report demonstrating that these dextromethorphan analogs are functional NMDA receptor antagonists in vivo. Given their potential therapeutic utility and favorable side-effect profiles, such low affinity NMDA receptor antagonists could be considered for further development in neurological (e.g., anticonvulsant) and psychiatric (e.g., antidepressant) disorders.
KW - Dextromethorphan analogs
KW - NMDA receptors
KW - NMDA seizures
KW - Sigma receptors
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U2 - 10.1016/j.pbb.2021.173154
DO - 10.1016/j.pbb.2021.173154
M3 - Article
C2 - 33609599
AN - SCOPUS:85101318690
VL - 203
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
SN - 0091-3057
M1 - 173154
ER -