The N-methyl-D-aspartate receptor (NMDAR) modulates a wide range of neurodegenerative and neuropsychiatric conditions, including Major Depressive Disorder, Parkinson’s disease, and Alzheimer’s disease. Existing treatment options for these disorders show suboptimal efficacy and varying levels of tolerability. As a result of these limitations, alternative therapies are being pursued. NMDAR antagonism is a viable pharmacotherapeutic strategy for central nervous system disorders, as exemplified by the use of amantadine for the treatment of Parkinson’s disease, and both Ketamine and its S enantiomer Esketamine for treatment of clinical depression. Since its FDA-approval for use in both Major Depressive Disorder and Treatment-Resistant Depression, the Ketamine pharmacophore has continued to gain increasing interest. Specifically, Ketamine and Esketamine are chemically classified as β-ketoarylcyclohexylamines. In spite of their clinical significance, the structure activity relationship studies on β-keto-arylcyclohexylamines as NMDAR antagonists are limited. To probe the pharmacophore and establish a foundation for compounds with optimized efficacy and tolerability, we have designed and synthesized a series of β-ketoarylcyclohexylamines. Currently, 18 compounds have been synthesized in 5 steps, and have been fully analytically characterized. NMDAR affinities for these compounds were evaluated using competitive radioligand binding assays, with affinities ranging from 105 to 508 nM. Binding on other CNS receptors will also be evaluated in order to better understand the polypharmacological binding profiles of these compounds, which can give insight into possible synergies and side effects. We also plan to investigate the pharmacokinetics and physicochemical properties of these compounds, with special interest in the in vitro metabolic variability, pKa, and lipophilicity profiles.

Design, syntheses, and pharmacological evaluations of β-ketoarylcyclohexylamines

ACS Fall 2021

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