APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology

Adams, John; Ramirez, Juan Ignacio; Shi, Yunqing; Thomsen, William J.; Frazer, John; Morgan, Michael; Edwards, Jeffrey E.; Chen, Weichao; Teegarden, Bradley R.; Xiong, Yifeng; Al-Shamma, Hussien; Behan, Dominic P.; Connolly, Daniel T.

doi:10.1124/jpet.109.153189

Cited by 23 publications

(29 citation statements)

References 23 publications

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“…No increase in bleeding time in the presence of APD791 was observed as compared with other antiplatelet therapies. Additionally, APD791 was able to block 5-HT-dependent platelet activation over a short time scale (2 h) (16,17). Our data provide mechanistic insight into the reduced aggregation previously observed in SSRI-treated patients and support explorations of peripherally restricted, well tolerated SSRIs or 5-HT 2A R antagonists as an antiplatelet therapeutic approach.…”

Section: -Ht 2a R Surface Expression Reduced With Lost Sert Functionmentioning

confidence: 74%

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Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Oliver

Duvernay

Hamm

et al. 2016

Journal of Biological Chemistry

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Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. In the periphery, serotonin (5-HT) 3 is produced by enterochromaffin cells in the gastrointestinal tract, released into the plasma, and quickly taken up by platelets via the plasma membrane serotonin transporter (SERT). Following uptake, 5-HT is stored in dense granules by the actions of the vesicular monoamine transporter 2 (1-4). Chronic inhibition of SERT through selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopram and paroxetine) leads to dramatically reduced platelet 5-HT granule content (5, 6), altering peripheral 5-HT homeostasis and potentially modifying multiple physiological processes including hemostasis (7-10). Clinically, increased bleeding risk has been observed in patients taking SSRIs, and platelet aggregation is disrupted (5, 11). Here, we have characterized a similar effect in two distinct mouse models of lost SERT function, suggesting that sustained loss of SERT function influences hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERTPlatelet dense granules contain 5-HT along with other platelet agonists including adenosine diphosphate (ADP), thromboxane (TXA2), and histamine. Appropriate platelet activation depends on the timely release of these factors (4, 5, 12). Platelet aggregation is crucial early in thrombus formation (4, 5, 13). Aggregation, which is the bridging of platelet-platelet contacts, requires a conformational alteration in the glycoprotein ␣IIb␤3, leading to its activation and fibrinogen binding. 5-HT has been shown to enhance aggregation in a 5-HT 2A receptor (5-HT 2A R)-dependent manner (4, 14 -17). The 5-HT 2A R is the only serotonergic receptor found on platelets and potentiates platelet responses to weak agonists like ADP (18). Subthreshold concentrations of two different platelet agonists can exert a synergistic effect on platelet activation. One example includes dual ADP and 5-HT activation leading to increases in cytosolic [Ca 2ϩ ] (13). However, the role of 5-HT during in vivo hemostasis remains unclear, particularly in the context of chronic SERT inhibition.To elucidate the underlying mechanisms of SSRI effects on platelet aggregation, a better understanding of acute versus chronic inhibition of SERT function during platelet activation is required. Acute and chronic blockage of SERT function results in distinct scenarios regarding the effects on 5-HT homeostasis. Acute inhibition of SERT blocks the amount of

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Section: -Ht 2a R Surface Expression Reduced With Lost Sert Functionmentioning

confidence: 74%

“…APD791, an inverse agonist of 5-HT 2A R, is currently in clinical trials and attenuated recurrent thrombosis irrespective of the time of treatment (16,17). No increase in bleeding time in the presence of APD791 was observed as compared with other antiplatelet therapies.…”

Section: -Ht 2a R Surface Expression Reduced With Lost Sert Functionmentioning

confidence: 99%

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Oliver

Duvernay

Hamm

et al. 2016

Journal of Biological Chemistry

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“…Inhibition of the 5-HT2A receptor, which is the main serotonin receptor on platelets and arterial smooth muscle cells, with ketanserin or the newer, more selective agents sarpogrelate and APD791 prevented occlusive arterial thrombus formation in several studies [30], [31], [32], [33]. The group around Willerson established that ketanserin inhibits serotonin-induced cyclic flow variations caused by platelet aggregation and vasoconstriction in a canine model of coronary artery stenosis and injury [34], [35], [36], [37], [38], [39].…”

Section: Discussionmentioning

confidence: 99%

Serotonin Antagonism Improves Platelet Inhibition in Clopidogrel Low-Responders after Coronary Stent Placement: An In Vitro Pilot Study

Duerschmied

Ahrens²,

Mauler³

et al. 2012

PLoS ONE

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Increased residual platelet reactivity remains a burden for coronary artery disease (CAD) patients who received a coronary stent and do not respond sufficiently to treatment with acetylsalicylic acid and clopidogrel. We hypothesized that serotonin antagonism reduces high on-treatment platelet reactivity. Whole blood impedance aggregometry was performed with arachidonic acid (AA, 0.5 mM) and adenosine diphosphate (ADP, 6.5 µM) in addition to different concentrations of serotonin (1–100 µM) in whole blood from 42 CAD patients after coronary stent placement and 10 healthy subjects. Serotonin increased aggregation dose-dependently in CAD patients who responded to clopidogrel treatment: After activation with ADP, aggregation increased from 33.7±1.3% to 40.9±2.0% in the presence of 50 µM serotonin (p<0.05) and to 48.2±2.0% with 100 µM serotonin (p<0.001). The platelet serotonin receptor antagonist ketanserin decreased ADP-induced aggregation significantly in clopidogrel low-responders (from 59.9±3.1% to 37.4±3.5, p<0.01), but not in clopidogrel responders. These results were confirmed with light transmission aggregometry in platelet-rich plasma in a subset of patients. Serotonin hence increased residual platelet reactivity in patients who respond to clopidogrel after coronary stent placement. In clopidogrel low-responders, serotonin receptor antagonism improved platelet inhibition, almost reaching responder levels. This may justify further investigation of triple antiplatelet therapy with anti-serotonergic agents.

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“…One such receptor is the serotonin 5-HT 2A receptor, which belongs to the 5-HT 2 receptor family. The 5-HT 2A receptors are of significant clinical interest because they are involved in the mediation of mental disorders [12], [13], and many cardiovascular diseases [14], [15]. To this end, it has been previously shown that inhibition of serotonin 5-HT 2A receptor can improve coronary patency in in-vivo model of recurrent thrombosis [16].…”

Section: Introductionmentioning

confidence: 99%

The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

et al. 2014

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There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis.

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APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology

Cited by 23 publications

References 23 publications

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor

Serotonin Antagonism Improves Platelet Inhibition in Clopidogrel Low-Responders after Coronary Stent Placement: An In Vitro Pilot Study

The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

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