DOI

https://doi.org/10.25772/MJQW-8C64

Author ORCID Identifier

0000-0002-2967-2017

Defense Date

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Richard A. Glennon

Abstract

Synthetic cathinones are stimulant drugs of abuse that act at monoamine transporters e.g. the dopamine transporter (DAT) as releasing agents or as reuptake inhibitors. More than >150 new synthetic cathinones have emerged on the clandestine market and have attracted considerable attention from the medical and law enforcement communities.

threo-Methylphenidate (tMP) is an FDA approved drug for the treatment of ADHD and narcolepsy, which also acts as a DAT reuptake inhibitor and is widely abused. tMP and synthetic cathinones share some structural similarities and extensive structure-activity relationship (SAR) studies on tMP have been conducted. However, much less is known about the SAR of synthetic cathinones, and the available MP literature might assist in understanding it. The main focus of this research was to compare SAR between methylphenidate-cathinone hybrids and available methylphenidate SAR in order to identify some guiding principles that might allow
us to predict their abuse potential and to identify which cathinones should be
targeted for more extensive evaluation. In the present study, we evaluated eight 2-benzoylpiperidine analogs and a descarbonyl analog to determine if tMP SAR can be applied to cathinone SAR. We conducted molecular modeling and docking studies and predicted the order of potency to be tMP > 2-benzoylpiperidine > 2-benzylpiperidine based on the number of hydrogen bonds. The synthesized analogs were evaluated in a competition assay using live-cell imaging against APP+ in HEK293 cells stably expressing hDAT. All compounds were found to be DAT reuptake inhibitors and, as the modeling studies predicted, the order of potency in our functional studies was also found to be tMP > 2-benzoylpiperidine > 2- benzylpiperidine. A significant correlation was obtained between the potency of the benzoylpiperidines and tMP binding data (r = 0.91) suggesting that the SAR of tMP analogs might be applicable to the synthetic cathinones as DAT reuptake inhibitors.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-9-2019

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