VHD-associated drugs

Figure 7.1 Chemical structures of VHD/PH-associated drugs that are also 5-HT2B receptor agonists. The chemical structures of all currently known VHD/PH-inducing drugs-all exhibit high-to-moderate 5-HT2B receptor agonist potency -are shown. MDMA and MDA are included as they behave similarly to VHD-associated drugs in vitro.

Three-dimensional representation of VHD-associated and non-VHD-associated drug affinity for a battery of GPCRs, ligand-gated ion channels, and biogenic amine transporters. 

Further evidence implicating 5-HT2b receptors in drug-associated VHD came in the years following our predictions. In 2003, we used primary cultures of human heart valve interstitial cells (hVICs) to assess whether fenfluramine and/or norfenfluramine induced cell proliferation - an in vitro approximation of the proliferative lesions found in the valves of VHD patients - in a 5-HT2b receptor-dependent manner [11], Treatment of primary hVIC cultures with either fenfluramine or norfenfluramine increased biochemical indices of cell proliferation, an effect that was blocked by cotreatment with a 5-HT2b receptor-selective antagonist [11]. 

VHD- and PH-associated risks (e g., the antiparkinsonian peigolide), drugs that inhibit, in a cell type-specific manner, the downstream mitogenic effectors of 5-HT2B receptor signaling might decrease the cardiopulmonary risks associated with such drugs. 

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