Design, Syntheses, and Pharmacological Evaluations of β-Ketoarylcyclohexylamines

Abstract

Neurological disorders are notoriously difficult to treat. The N-methyl-D-aspartate receptor (NMDAR) modulates a wide range of neurodegenerative and neuropsychiatric conditions, including Major Depressive Disorder (MDD), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Existing treatment options for these disorders show suboptimal efficacy and low levels of tolerability. As a result of these limitations, alternative therapies are being pursued. NMDAR antagonism is a viable pharmacotherapeutic strategy for CNS disorders, as exemplified by amantadine for the treatment of PD, memantine for AD, and ketamine for depression. Since its FDA-approval for use in both MDD and treatment-resistant depression, the ketamine pharmacophore has continued to garner increasing interest. Specifically, ketamine and its (S)-enantiomer, Esketamine, are chemically classified as β-ketoarylcyclohexylamines. Despite their clinical significance, the pharmacological exploration of this class of compounds is limited. To probe the pharmacophore and establish a foundation for compounds with optimized efficacy and tolerability, we have designed, synthesized, and pharmacologically evaluated a series of β-ketoarylcyclohexylamines. 24 compounds have been synthesized in 4-5 steps, and have been fully analytically characterized. NMDAR affinities of these compounds were evaluated using competitive radioligand binding assays, with affinities ranging from about 50 to 2500 nM, thereby demonstrating therapeutic potential.