The N-methyl-D-aspartate receptor (NMDAR) modulates an extensive range of neurodegenerative and neuropsychiatric conditions, including Major Depressive Disorder (MDD) and Alzheimer’s Disease (AD). Existing treatment options for these disorders show minimal to moderate efficacy and varying levels of tolerability. As a result of these limitations, alternative therapies are being actively pursued. NMDAR antagonism is a viable pharmacotherapeutic strategy for central nervous system disorders, as exemplified by the use of memantine for the treatment of AD. Moreover, esketamine, an NMDAR antagonist, was recently FDA-approved for use in treatment-resistant depression. Racemic ketamine is currently used as a general anesthetic in surgery. Ketamine is chemically classified as a β-keto-arylcyclohexylamine. In spite of their clinical significance, the structure activity relationship studies on β-keto-arylcyclohexylamines as NMDAR antagonists are limited. To elucidate the pharmacophore and find agents with improved efficacy and tolerability, we have designed and synthesized a series of β-keto-arylcyclohexylamines. Currently, 12 compounds have been synthesized, each in 5 steps, with a final step yield of 31-72% from starting materials.  Each final compound was analytically characterized with 1D and 2D NMR, GC-MS, and HR-MS. NMDAR affinities of these compounds were evaluated using competitive radioligand binding assays, with affinities ranging from 105 to 508 nanomolar. Additional receptor affinities to be investigated include the serotonin (5-H2A), opioid receptors, sigma-1 and sigma-2 receptors, and monoamine reuptake transporters DAT, NET, and SERT. To identify potential therapeutic effects, further in vitro and in vivo studies and physicochemical assays will be undertaken on compounds with desired polypharmacological profiles.<br/>

Design, syntheses, and structure activity relationship studies of β-keto-arylcyclohexylamines as NMDAR antagonists

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.