5-HT2B Receptor-mediated Cardiac Valvulopathy

Author

Pallavi Nistala, VCU School of Pharmacy, Dept. of Medicinal ChemistryFollow

DOI

https://doi.org/10.25772/0YNR-6690

Defense Date

2018

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmaceutical Sciences

First Advisor

Dr. Malgorzata Dukat

Second Advisor

Dr. Richard A. Glennon

Abstract

5-HT_2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens and determined their affinities at the three types of 5-HT₂ receptors. A high correlation was found between the affinities of these molecules at 5-HT_2A and 5-HT_2B receptors. Therefore, these hallucinogens have a high possibility of causing valvulopathy, which gives rise to a new class of valvulopathogens.

Since certain hallucinogens have the common phenylisopropylamine structural scaffold as that of MDA and norfenfluramine, we conducted 3D-QSAR studies to identify the common structural features of these molecules that are responsible for their high affinities. We were unable to obtain a suitable CoMFA and CoMSIA model for 5-HT_2B receptors, but we were able to obtain an internally and externally validated model for 5-HT_2A receptor affinities which indicated the hydrophobicity of the substituent at the 4- position was essential for high affinity. Following up with this evidence, we conducted a correlation analysis for the hydrophobicity (π-value) of the 4-position substituent and found a positive correlation between the π-value and the affinity of the molecules. The same results were not observed for the volume of the substituents.

We docked the molecules into the 5-HT_2B receptor and successfully generated models of the putative interactions made by the DOX molecules and the receptor. In order to compare their binding modes with respect to known valvulopathogens, we also generated models for norfenfluramine and MDA. Our docking results revealed that DOX molecules bind in a more or less similar manner to valvulopathogens MDA and norfenfluramine. Ours is the first in silico model developed for the potent valvulopathogen MDA and the hallucinogenic DOX series of molecules.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-14-2018