DOI

https://doi.org/10.25772/0HV0-SN48

Defense Date

2022

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmaceutical Sciences

First Advisor

Dr.Małgorzata Dukat

Second Advisor

Dr. Richard Glennon

Third Advisor

Dr. Javier Gonzalez-Maeso

Abstract

Recently, it has been reported that ligands of the 5-HT2A receptor can have drastic and fast-acting efficacy towards a number of different mental health disorders, such as depression and anxiety. A mixture of Amazonian plants calledayahuasca contains multiple compounds which have been shown to interact with the serotonergic system, and the 5-HT2Areceptor in particular.

The structurally similar compounds (DMT, harmine, harmaline, and tetrahydroharmine) found in ayahuasca were examined for differences in their physiochemical properties that might contribute to their binding affinity for the 5-HT2Areceptor. 3D Molecular modeling and docking studies of these compounds were conducted to predict their relative binding modes in relation to one another, and to validate previously proposed 2D binding modes.

Published studies of the binding affinities of both dimethyltryptamine (i.e., DMT) derivatives as well as the harmala alkaloids (harmine, harmaline, tetrahydroharmine) provided data points from which correlations were used to support the relative binding modes. Additional bromo-substituted DMT analogs were synthesized and assayed at cloned human 5-HT2A receptors for binding affinity. The binding affinity data provided additional data points for our QSAR studies necessary to provide statistical significance to these correlations. Our results indicated that 5-Br DMT (Ki = 45 nM) binds with the highest affinity for this receptor, followed by 4-Br DMT (Ki = 62 nM), 7-Br DMT (Ki = 353 nM), and 6-Br DMT (Ki = 814 nM). The major constituents of ayahuasca were also tested in a calcium mobilization assay at the 5-HT2A receptor to determine general agonist or antagonist activity. DMT was found to be a partial agonist, while harmine and harmaline produced no calcium mobilization in this assay. Tetrahydroharmine was shown for the first time to be an antagonist in any known 5-HT2A receptor downstream signaling assays. Full characterization of each of these compounds at all major downstream signaling assays will need to be conducted to determine whether they might elicit an antidepressant effect via any 5-HT2A mediated pathway.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

4-29-2022

Available for download on Saturday, April 29, 2023

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