Defense Date

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Malgorzata Dukat

Abstract

2-(Benzoyl)piperidines (BPs) are at a crossroads of therapy and abuse. These compounds are a hybrid between the ADHD medication methylphenidate and abused stimulant cathinones. Here we use computational molecular modeling, synthesis, mutagenesis, and epifluorescence microscopy to further improve the understanding of and potential treatments for several neuropsychiatric disorders. Utilizing the BP scaffold and controlling chirality and aryl substitution, these agents were examined at DAT and SERT. From these investigations it has now been established that R isomer BPs are favored for DAT while S isomer BPs are favored for SERT. Aryl-substitution can greatly affect the selectivity of these agents with a m-chloro-substituent having the ability to partake in halogen bonding interactions with SER149 in DAT, thus increasing its DAT activity whereas the benz-fused substituent was able to vastly increase activity at SERT. The nature of BPs interaction with SERT has also been elucidated, demonstrating reuptake inhibition. Due to the predictability and spectrum in selectivity, this series of agents is well suited to be further investigated for therapeutic potential and the study of neuropsychiatric disorders.

Recently, it has been reported that agonists of the 5-HT2A receptor elicit fast-acting and long-lasting efficacy towards treatment resistant depression. A bygone antidepressant agent, alpha-ethyltryptamine (a-ET), was chosen to be reevaluated with the aid of current medicinal chemistry techniques. Stereoisomers and substituted analogs of a-ET (4- and 5-bromo and methoxy) were examined using 3D molecular modeling and docking studies to predict their relative binding modes to each other and elucidate protein-ligand interactions that might contribute to binding affinity and agonist activity at 5-HT2A receptors. To validate the computational studies and previously published activity data, a-ET and analogs were synthesized and assayed at cloned human 5-HT2A receptors for binding affinity and agonist activity. For the first time, binding affinity data have been provided for this class of compounds. Our results indicated that all analogs examined bind at 5-HT2A receptors, and all compounds exhibit partial agonist activity except for racemic and (R) a-ET. These two agents bind at 5-HT2A receptors but failed to show any activity in a calcium mobilization assay. Future examination of these compounds will be required to determine whether they might be non-hallucinogenic agents that elicit rapid and long-lasting antidepressant effects via a 5-HT2A receptor mediated pathway.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-9-2024

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