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The Emergence of 5-HT2B Receptors as Targets to Avoid in Designing and Refining Pharmaceuticals

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The Serotonin Receptors

Part of the book series: The Receptors ((REC))

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Abstract

The long-term use of certain drugs, such as fenfluramine, dihydroergotamine, and pergolide, has been associated with an increased risk for valvular heart disease (VHD) and pulmonary hypertension (PH). Recent investigations have implicated the 5-hydroxytryptamine2B (5-HT2B) receptor in the pathogenesis of VHD and PH. Specifically, the activation of 5-HT2B receptors by VHD- and PH-associated drugs leads to proliferative lesions in the valves of the heart and the pulmonary arterial wall, respectively. For heart valve interstitial cells in vitro, mitotic responses to fenfluramine and its metabolite norfenfluramine have been demonstrated and shown to be mediated almost exclusively by 5-HT2B receptor activation. Furthermore, the activity at recombinant 5-HT2B receptors appears sufficient to predict the ability of a drug to induce mitosis in heart valve interstitial cells in vitro and, likely, VHD-inducing potential in humans.

In mice, hypoxia-induced smooth muscle cell proliferation that gives rise to pulmonary hypertension has been shown genetically and pharmacologically to require 5-HT2B receptors. Additionally, hypoxia-induced pulmonary artery remodeling in mice is significantly exacerbated by prolonged treatment with the PH-associated drug fenfluramine, likely the result of high plasma levels of the metabolite norfenfluramine, a more potent and efficacious 5-HT2B receptor agonist than the parent compound. Thus, drug-induced PH and VHD both seem to result from activation ofmitogenic 5-HT2B receptors by the parent compound and/or an active metabolite. As such, current and novel pharmaceuticals and their metabolites that are 5-HT2B receptor agonists should not be used in humans because of their likelihood to induce fenfluraminelike VHD and PH.

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  1. Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Vincent Setola & Bryan L. Roth

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    Bryan L. Roth MD, PhD

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Setola, V., Roth, B.L. (2006). The Emergence of 5-HT2B Receptors as Targets to Avoid in Designing and Refining Pharmaceuticals. In: Roth, B.L. (eds) The Serotonin Receptors. The Receptors. Humana Press. https://doi.org/10.1007/978-1-59745-080-5_13

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