Products Cited in Publications Worldwide Structure Activity Relationship (SAR) Studies of 1, 2-Diarylethylamines as N-Methyl-D-Aspartate Receptor Antagonists

Structure Activity Relationship (SAR) Studies of 1, 2-Diarylethylamines as N-Methyl-D-Aspartate Receptor Antagonists

Michael B. Dybek

Abstract

Memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist is FDA approved for the treatment of moderate to severe Alzheimer disease. The efficacy is believed to stem from its ability to block/mitigate excitotoxicity that stems from excessive glutamatergic activation/transmission and is thus neuroprotective. However, they display tolerability issues that hinder their ability to be utilized as neuroprotective agents. Previous studies from our lab suggest that the compounds that function as uncompetitive NMDAR antagonists and have moderate affinity to the NMDAR demonstrate the best tolerability. This observation has prompted investigations for novel neuroprotective NMDAR antagonists with improved efficacy and tolerability. Our lead compounds phencyclidine (PCP) and analogs have demonstrated the ability to protect hippocampal neurons from NMDA insult in vitro. Our studies explored synthesizing and evaluating both arylalkylamines and 1,2-diarylethylamines. A total of 76 target compounds were synthesized as part of this exploration. In vitro competitive radio-ligand binding assays were conducted for each compound to determine affinities to NMDAR in rat forebrain homogenate. Several of these compounds demonstrated binding affinities within a previously defined target range (400 nM – 2,100 nM). This range was previously determined to provide the highest tolerability for uncompetitive NMDAR antagonists. 34 compounds were further evaluated to obtain binding affinities on 44 other relevant central nervous system targets. This SAR investigation has uncovered several intriguing polypharmacological profiles have emerged, including potent affinities to NMDAR, dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT).

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3-Fluorobenzaldehyde

A211523456-48-496% GC

3-Fluorobenzaldehyde

84.0/500g

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A580150446-52-698%

2-Fluorobenzaldehyde

150.0/500g

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4-Fluorobenzaldehyde

A781101459-57-495%

4-Fluorobenzaldehyde

78.0/500g

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A96496834645-25-595%

(1R)-1,2-Diphenylethan-1-amine

134.0/1g

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