Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor antagonist R-102444

Ogawa, Taketoshi; Sugidachi, Atsuhiro; Tanaka, Naoki; Fujimoto, Koichi; Asai, Fumitoshi

doi:10.1016/s0014-2999(02)02654-7

Cited by 36 publications

(27 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Whereas APD791 had no effect on ADP-induced aggregation per se, it was a potent inhibitor of 5-HT-mediated amplification. Similar results have been reported for other less selective 5-HT 2A antagonists including ketanserin, sarpogrelate (M-1), R-96544, SR 46349, and AR246686 (Van Nueten et al, 1981;Herbert et al, 1993;Ogawa et al, 2002;Adams et al, 2008). The IC 50 of APD791 inhibition of human platelet aggregation (8.7 nM) was consistent with its K i for the human 5-HT 2A receptor (4.9 nM).…”

Section: Discussionsupporting

confidence: 84%

See 1 more Smart Citation

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

Ramirez²,

Shi³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl-)benzamide] a novel 5-hydroxytryptamine 2A (5-HT 2A ) receptor antagonist. APD791 displayed high-affinity binding to membranes (K i ϭ 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC 50 ϭ 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT 2A receptor. In competition binding assays, APD791 was greater than 2000-fold selective for the 5-HT 2A receptor versus 5-HT 2C and 5-HT 2B receptors, and was inactive when tested against a wide panel of other G-protein-coupled receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC 50 ϭ 8.7 and 23.1 nM, respectively).Similar potency was observed for inhibition of 5-HT-stimulated DNA synthesis in rabbit aortic smooth muscle cells (IC 50 ϭ 13 nM) and 5-HT-mediated vasoconstriction in rabbit aortic rings. Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT 2A receptor antagonist with potent activity on platelets and vascular smooth muscle.Serotonin (5-hydroxytryptamine, 5-HT) is a naturally occurring indoleamine found primarily in brain, enterochromaffin tissue, and platelets. 5-HT exerts a multitude of biological effects mediated through interaction with specific cell surface G-protein-coupled receptors (GPCRs). To date, at least 14 different human 5-HT GPCRs are known (Kaumann and Levy, 2006). Among them, 5-HT 2A receptors on vascular smooth muscle cells and platelets play an important role in the regulation of cardiovascular function.The uptake process and storage capacity for 5-HT by platelets are such that minimal amounts of the amine exist in normal plasma. However, upon platelet activation at sites of vessel injury, 5-HT is released from the dense granules in platelets (Ashton et al., 1986). Although 5-HT by itself is only a weak activator of platelet aggregation, it effectively amplifies aggregation induced by other agonists including collagen, ADP, epinephrine, and thrombin (De Clerck and Herman, 1983;De Clerck and Janssen, 1990). Thus, 5-HT This work was supported by Arena Pharmaceuticals, Inc. Article, publication date, and citation information can be found at

show abstract

Section: Discussionsupporting

confidence: 84%

“…The platelet and smooth muscle responses to 5-HT have been shown to be mediated predominantly by the 5-HT 2A receptor (Yang et al, 1996;Pawlak et al, 1998;Ogawa et al, 2002;Nishihira et al, 2006). Thus, it is reasonable to explore the potential beneficial therapeutic effects of 5-HT 2A receptor antagonists in patients with cardiovascular disease.…”

mentioning

confidence: 99%

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

Ramirez²,

Shi³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The R-96544 antagonist has a pA 2 = 10.4 for the 5-HT 2A receptors, with low affinity for other subtypes of 5-HT receptors; furthermore, it practically does not bind to the dopamine or adrenergic receptors (16). Regarding SB-204741, the pK values for 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors are 5.3, 8.0, and 5.8, respectively (20,23).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, SB-204741 caused a small, although statistically significant, increase in resting heart rate, suggesting that the 5-HT 2B receptors could have a role in the tonic control of heart rate, even though they do not seem to act on reflex situations. However, there is no published study using these drugs by the ic route, and the doses used here were adapted from studies employing other routes (16,17,24). Therefore, a definitive answer concerning the role of 5-HT 2A receptors (and the lack of a role of 5-HT 2B receptors) in the modulation of vagal bradycardia will require that different selective antagonists be administered at different doses.…”

Section: Discussionmentioning

confidence: 99%

“…These studies have provided some evidence that the 5-HT 2B receptors excite while the 5-HT 2C receptors inhibit the neurons of the nucleus tractus solitarii (NTS) (1,8,12,15). In the present report, we describe the effects of central administration of the selective ligands R-96544 (a 5-HT 2A receptor antagonist) (16) and SB-204741 (a 5-HT 2B receptor antagonist) (17) on the reflex vagal bradycardia elicited by activation of cardiopulmonary efferents with iv PBG.…”

mentioning

confidence: 86%

See 1 more Smart Citation

Central 5-HT2A receptors modulate the vagal bradycardia in response to activation of the von Bezold-Jarisch reflex in anesthetized rats

Neto

Macêdo

Silva

et al. 2011

Braz J Med Biol Res

View full text Add to dashboard Cite

The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5-HT_2Aand 5-HT_2Cserotonergic receptors in post-ictal antinociception

Freitas

Oliveira

et al. 2013

Synapse

View full text Add to dashboard Cite

The periaqueductal gray matter (PAG) consists in a brainstem structure rich in 5-hydroxytryptamine (5-HT) inputs related to the modulation of pain. The involvement of each of the serotonergic receptor subtypes found in PAG columns, such as the dorsomedial (dmPAG) and the ventrolateral (vlPAG) columns, regarding post-ictal antinociception have not been elucidated. The present work investigated the participation of the dmPAG and vlPAG columns in seizure-induced antinociception. Specifically, we studied the involvement of serotonergic neurotransmission in these columns on antinociceptive responses that follow tonic-clonic epileptic reactions induced by pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl(-) influx antagonist. Microinjections of cobalt chloride (1.0 mM CoCl2 /0.2 µL) into the dmPAG and vlPAG caused an intermittent local synaptic inhibition and decreased post-ictal antinociception that had been recorded at various time points after seizures. Pretreatments of the dmPAG or the vlPAG columns with the nonselective serotonergic receptors antagonist methysergide (5.0 µg/0.2 µL) or intramesencephalic microinjections of ketanserin (5.0 µg/0.2 µL), a serotonergic antagonist with more affinity to 5-HT2A/2C receptors, decreased tonic-clonic seizure-induced antinociception. Both dmPAG and vlPAG treatment with either the 5-HT2A receptor selective antagonist R-96544 (10 nM/0.2 µL), or the 5-HT2C receptors selective antagonist RS-102221 (0.15 µg/0.2 µL) also decrease post-ictal antinociception. These findings suggest that serotonergic neurotransmission, which recruits both 5-HT2A and 5-HT2C serotonergic receptors in dmPAG and vlPAG columns, plays a critical role in the elaboration of post-ictal antinociception.

show abstract

Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor antagonist R-102444

Cited by 36 publications

References 20 publications

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

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

Central 5-HT2A receptors modulate the vagal bradycardia in response to activation of the von Bezold-Jarisch reflex in anesthetized rats

The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5-HT_2Aand 5-HT_2Cserotonergic receptors in post-ictal antinociception

Contact Info

Product

Resources

About

Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor antagonist R-102444

Cited by 36 publications

References 20 publications

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

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

Central 5-HT2A receptors modulate the vagal bradycardia in response to activation of the von Bezold-Jarisch reflex in anesthetized rats

The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5-HT2Aand 5-HT2Cserotonergic receptors in post-ictal antinociception

Contact Info

Product

Resources

About

The role of dorsomedial and ventrolateral columns of the periaqueductal gray matter and in situ 5-HT_2Aand 5-HT_2Cserotonergic receptors in post-ictal antinociception