["discovering the Molecular and Cellular Mechanisms Underlying Fenfluramine-induced Cardiopulmonary Side Effects"]
Year: 2005
Type: article
Abstract: VINCENT SETOLA G protein-coupled receptors (GPCRs) are plasma membrane proteins that act as sensors for extracellular stimuli (e.g., photons, neurohumoral moduluators, odorants and tastants, lipids).The cognate stimulus for a GPCR induces a conformational change that catalyzes, via heterotrimeric G proteins, a series of biochemical reactions inside the cell (i.e., a response); the responses can lead to phenomena such as differentiation, morphological changes, chemotaxis, and mitosis.G protein-coupled receptors are the targets of, in addition to endogenous neurohumoral molecules, more than 30% of currently marketed pharmaceutical drugs.For instance, the effective appetite suppressant fenfluramine reduces appetite via activation of serotonin (5-hydroxytryptamine, 5-HT) 2C (5-HT 2C ) receptors.Fenfluramine was, despite its efficacy as an anorexigen, withdrawn from market due to its association with life-threatening cardiovascular side effects [i.e., valvular heart disease (VHD) and pulmonary hypertension (PH)].The work presented in this thesis describes efforts to identify the cellular and molecular mechanisms responsible for fenfluramine-induced VHD.Evidence is presented that both fenfluramine and, to a greater extent, its major in vivo metabolite norfenfluramine, activate mitogenic 5-HT 2B receptors, which are expressed in human heart valve interstitial cells (VICs).Both fenfluramine and norfenfluramine induce mitogenic responses from VICs in vitro that are abrogated by a 5-HT 2B receptor antagonist.Further, xvii data implicating van der Waals' (vdW) interactions between the α-methyl group of S-(+)norfenfluramine and a valine in the second transmembrane helix of the receptor (V2.53) in the compound's valvulopathic-but not anorexigenic-effects are described.The implication of the findings described herein on preventing drug-associated cardiopulmonary side effects and developing safe, effective anorexigens are also discussed.
Author: Vincent Setola
Institution: Case Western Reserve University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1957261096