C-122, a novel antagonist of serotonin receptor 5-HT2B, prevents monocrotaline-induced pulmonary arterial hypertension in rats

Zopf, David; Neves, Liomar A. A.; Nikula, Kristen J.; Huang, Jinbao; Senese, Peter B.; Gralinski, Michael

doi:10.1016/j.ejphar.2011.08.015

Cited by 35 publications

(25 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The 5-HT 2B receptor is up-regulated in pulmonary arteries removed from PAH patients and the development of hypoxia-induced PAH is inhibited in mice deficient in the 5-HT 2B receptor (Dumitrascu et al, 2011;Launay et al, 2002). Pharmacological inhibition of 5-HT 2B retards the development of PAH in hypoxic or monocrotaline exposed rodents (Dumitrascu et al, 2011;Porvasnik et al, 2010;Zopf et al, 2011).…”

Section: Lessons From Disappointments 31 Terguridementioning

confidence: 99%

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Lythgoe

Rhodes

Ghataorhe

et al. 2016

Pharmacology & Therapeutics

View full text Add to dashboard Cite

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). But against this backdrop there have been some notable disappointments in drug development. Here we use these as case studies to emphasise the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies and the value of deep-phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of 'omics' technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.

show abstract

Section: Lessons From Disappointments 31 Terguridementioning

confidence: 99%

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Lythgoe

Rhodes

Ghataorhe

et al. 2016

Pharmacology & Therapeutics

View full text Add to dashboard Cite

show abstract

“…16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduced pulmonary pressure, arterial wall thickening, and lumen occlusion but maintained cardiac function. [17][18][19] Independently, 5-HT was shown to stimulate human BM stromal cells and synergize with other pleiotropic growth factors that promote hematopoietic stem and progenitor cells. 20 The 5-HT action on hematopoiesis or BM microenvironment at pathophysiologic conditions warrant further investigation.…”

Section: Introductionmentioning

confidence: 99%

“…16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduced pulmonary pressure, arterial wall thickening, and lumen occlusion but maintained cardiac function. [17][18][19] Independently, Submitted June 2, 2011; accepted December 15, 2011. Prepublished online as Blood First Edition paper, December 20, 2011; DOI 10.1182 DOI 10.…”

mentioning

confidence: 99%

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Launay

Hervé

Crinon

et al. 2012

Blood

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is IntroductionPulmonary arterial hypertension (PAH) is a rare but fatal disease, often of unknown origin, characterized by progressive increase in pulmonary vascular resistance and remodeling associated with vasoconstriction. 1 PAH is histologically characterized by a neomuscularization of small pulmonary arteries with intimal thickening, medial hypertrophy, adventitial proliferation, and abnormal extracellular matrix deposition. The progression of vascular remodeling results in vascular lumen narrowing, increased pulmonary artery resistance, hypoxia, and right heart hypertrophy, although the molecular pathways initiating this remodeling are not clearly established.On the one hand, stem cells, resident or not, may give rise to a significant proportion of differentiating/proliferating smooth muscle cells (SMCs) that contribute to intimal hyperplasia in lung vascular remodeling. 2 Moreover, genetic ablation of the transmembrane tyrosine kinase receptor for stem cell factor/c-kit pathway results in a marked reduction in intimal hyperplasia in animal models of vascular injury; conversely, wild-type (WT) bone marrow (BM) reconstitution in c-kit mutant mice led to intimal hyperplasia comparable with WT animals. 3 Pharmacologic antagonism of the c-kit pathway with STI-571 (imatinib mesylate; Gleevec) also results in a marked reduction in hyperplasia. 3 Mobilization of c-kit expressing cells from BM to blood circulation is a physiologic response to hypoxia. Increasing evidence supports the idea that these progenitor cells of BM origin may also contribute to vascular wall remodeling that is characteristic of PAH. [4][5][6][7][8] However, it is unclear, whether this entry of progenitors represents a protective or a worsening process in the development of PAH. 9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH. 14 Therapeutic drugs with PAH as a side effect, such as the amphetamine derivative and anorexigen dexfenfluramine, are potent 5-HT releasers acting at 5-HT transporter (SERT) and/or agonists at 5-HT receptors (5-HTRs). 15 An over-expression of 5-HT 2B Rs is observed in PAH. 16 Blockade of 5-HT 2B Rs using independent approaches, either genetic (5-HT 2B R knock-out mice; 5-HT 2B Ϫ/Ϫ ) or pharmacologic (5-HT 2B antagonist RS-12744) inactivation, completely prevented the development of hypoxia-induced pulmonary hypertension in mice. 16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduc...

show abstract

“…19 A pathophysiological role of 5-HT2B receptor (5-HT2BR) was suggested by the increased binding to 5-HT2BR in lung vascular bed of the hypoxia-induced PAH mouse model and corroborated by the results that genetic or pharmacological inactivation of 5-HT2BR prevented the development of PAH in mice. [20][21][22][23][24][25][26] 5-HT2BR is currently under active investigation as a therapeutic target for PAH. However, there is currently no evidence of 5-HT2BR-mediated constriction of pulmonary arteries in PAH.…”

mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

Liu

Tian²,

Mao³

et al. 2012

Hypertension

View full text Add to dashboard Cite

C-122, a novel antagonist of serotonin receptor 5-HT2B, prevents monocrotaline-induced pulmonary arterial hypertension in rats

Cited by 35 publications

References 36 publications

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

Contact Info

Product

Resources

About