Functions of 5-HT2A receptor and its antagonists in the cardiovascular system

doi:10.1016/j.pharmthera.2004.08.005

Pharmacology & Therapeutics

Volume 104, Issue 1, October 2004, Pages 59-81

https://doi.org/10.1016/j.pharmthera.2004.08.005 Get rights and content

Abstract

The serotonin (5-hydroxytryptamine, 5-HT) receptors have conventionally been divided into seven subfamilies, most of which have several subtypes. Among them, 5-HT_2A receptor is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Accordingly, selective 5-HT_2A antagonists may have potential in the treatment of cardiovascular diseases. Sarpogrelate, a selective 5-HT_2A antagonist, has been introduced clinically as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis. Molecular modeling studies also suggest that sarpogrelate is a 5-HT_2A selective antagonist and is likely to have pharmacological effects beneficial in the treatment of cardiovascular diseases. This review describes the above findings as well as the signaling linkages of the 5-HT_2A receptors and the mode of agonist binding to 5-HT_2A receptor using data derived from molecular modeling and site-directed mutagenesis.

Introduction

5-Hydroxytryptamine (5-HT, serotonin) is an indoleamine neurotransmitter and was identified in 1948. Serotonin was given as the name of the vasoconstrictor substance that appears in serum after blood has clotted, and enteramine as that of the smooth muscle-contracting substance present in enterochromaffin cells of the gut mucosa. The synthesis of 5-HT in 1951 permitted the identification of serotonin and enteramine as the same metabolite of 5-hydroxytryptophan. 5-HT has been identified for almost 55 years as an effector for various types of smooth muscle and subsequently, as an agent that enhances platelet aggregation and as a neurotransmitter in the central nervous system (CNS; Sanders-Bush & Mayer, 1996). 5-HT is found in both the central nervous system and the peripheral nervous system, and is important for a variety of physiological functions, including platelet aggregation, smooth muscle contraction, appetite, cognition, perception, mood, and other CNS functions (Hoyer et al., 1994, Roth, 1994). These diverse physiological functions are mediated by large number of 5-HT receptor subtypes that are encoded by distinct genes. It now appears that there are at least 15 receptor subtypes that belong to four classes of receptors: 5-HT_1/5, 5-HT_{2 (A, B, C)}, 5-HT₃, and 5-HT_4/6/7 (Hoyer et al., 1994). 5-HT_2A receptors are expressed in the CNS and periphery. The 5-HT_2A receptor mediates 5-HT-induced platelet aggregation, vascular and nonvascular smooth muscle contraction, perception, and emotion (Roth et al., 1998). It has been implicated in the pathogenesis of a wide variety of ischemic heart diseases.

This review article will emphasize the following topics: receptor classification, 5-HT receptors in the cardiovascular diseases, several 5-HT_2A antagonists, their pharmacological actions and molecular aspects, the signaling pathway of the 5-HT_2A receptor, and the clinical significance of 5-HT_2A receptor and its antagonists.

Section snippets

Serotonin receptor subtypes

The structural, operational, and transductional characteristics of 5-HT receptors are the main three criteria to classify these molecules in a comprehensive manner (Hoyer & Martin, 1996). The IUPHAR classification of receptors for 5-HT proposed at the 3rd Serotonin Satellite Meeting in Chicago and discussed in detail by Hoyer et al. (1994) is summarized in Table 1. 5-HT is divided into seven major classes, 5-HT_1–7, most of which have several subtypes.

Serotonin receptors in the cardiovascular system

The effects of serotonin in the cardiovascular system are complex. It is involved in both central and peripheral mechanisms, acting through numerous receptor subtypes. Its cardiovascular effects have been associated with bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction. 5-HT also acts as an ideal neurotransmitter candidate for many aspects of cardiovascular regulation. Recent pharmacological studies have suggested that compounds acting on 5-HT

5-Hydroxytryptamine_2A receptor and its antagonists

Serotonin is known to participate in the regulation of the cardiovascular system and is therefore linked to both vascular and cardiac events (Viekenes et al., 1999). Among the 5-HT receptors, 5-HT_2A receptor subtype mediates several important pathophysiological effects in both the peripheral nervous system and CNS. After vascular injury, the released 5-HT induces vasoconstriction, platelet aggregation, increase of vascular permeability and cell proliferation. Moreover, factors such as age,

Signaling pathway of 5-hydroxytryptamine_2A receptor

A total of 15 serotonin receptor subtypes have been reported to date, and they may be further subdivided into seven receptor classes. These subfamilies have been characterized according to overlapping pharmacological properties, amino acid sequences, gene organization, and second messenger coupling pathways (Hoyer et al., 1994). The 5-HT₁, 5-HT₂, 5-HT₄, 5-HT₅, 5-HT₆, and 5-HT₇ receptors couple to G-proteins, whereas the 5-HT₃ receptors are 5-HT-gated ion channels. Recent studies have revealed a

Molecular aspects of 5-hydroxytryptamine_2A receptors

The 5-HT_2A receptor is a member of the G protein-coupled receptor superfamily, for which structure-activity studies have identified key interactions in the ligand-receptor complexes. One notable group of ligands for this receptor are the serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and N,N-dimethyl 5-HT (bufotenin), which have high affinity for the 5-HT_2A receptor. Studying the binding pocket of the receptor and identifying the molecular mechanisms that determine ligand

Chemistry of sarpogrelate

Chemically, sarpogrelate is (±)-1-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-3-(dimethyl amino)-2-propyl hydrogen succinate hydrochloride (Fig. 1). In rats, dogs, monkeys, and man, oral sarpogrelate is first hydrolyzed to (±)-1-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-3-(dimethyl amino)-2-propanol (M-1; Komatsu et al., 1992). M-1 is a major metabolite, formed by displacement of the succinate ester portion from sarpogrelate. M-1 exhibited a more potent antiserotonergic effect on in vitro platelet

Clinical significance of 5-hydroxytryptamine_2A receptor and its antagonists

5-HT has important effects on cardiovascular function. It stimulates platelet aggregation and has a prothrombic effect. It potentiates platelet aggregation in the presence of other agonists, such as collagen, ADP, epinephrine, and thrombin (De Clerk et al., 1982, Holmsen, 1985). 5-HT is also known to be a strong vasoconstrictor at sites of endothelial injury (Van Nueten et al., 1981). Therefore, during thrombus formation, platelet-derived 5-HT plays an important role in creating a positive

Conclusion

This review describes the potential involvement of 5-HT_2A receptors in mediating many cardiovascular processes and diseases, including the contraction of vascular smooth muscle, platelet aggregation, thrombus formation, and coronary artery spasm. Sarpogrelate is a more selective and specific 5-HT_2A receptor antagonist than other 5-HT_2A antagonists and is an excellent drug for the treatment of peripheral vascular disease. Molecular modeling studies have provided the first structural hypothesis

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Review articleFunctions of 5-HT2A receptor and its antagonists in the cardiovascular system

Abstract

Introduction

Section snippets

Serotonin receptor subtypes

Serotonin receptors in the cardiovascular system

5-Hydroxytryptamine2A receptor and its antagonists

Signaling pathway of 5-hydroxytryptamine2A receptor

Molecular aspects of 5-hydroxytryptamine2A receptors

Chemistry of sarpogrelate

Clinical significance of 5-hydroxytryptamine2A receptor and its antagonists

Conclusion

Neuropharmacology

J Biol Chem

Eur J Pharmacol

Methods Neurosci

Eur J Pharmacol

Eur J Pharmacol

Trends Pharmacol Sci

Eur J Pharmacol

Life Sci

Neuroscience

Neuropsychopharmacology

Eur J Pharmacol

Eur J Pharmacol

Mol Brain Res

FEBS Lett

Eur J Pharmacol

Neuropharmacology

Pharmacol Biochem Behav

J Biol Chem

Eur J Pharmacol

Eur J Pharmacol

Lancet

J Biol Chem

Neuropharmacology

Neurochem Int

Trends Pharmacol Sci

Atherosclerosis

TIPS

Eur J Pharmacol

Brain Res

Cell-specific coupling of the cloned human 5-HT1F receptor to multiple signal transduction pathways

Naunyn-Schmiedeberg's Arch Pharmacol

Involvement of 5-HT1B and 5-HT1D receptors in sumatriptan mediated vasocontractile response in rabbit common carotid artery. 4

Br J Pharmacol

5-HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle

Naunyn-Schmiedeberg's Arch Pharmacol

Ritanserin, a 5-HT2 receptor antagonist, increases subcortical blood flow following photothrombotic middle cerebral artery occlusion in rats

Neurol Res

Arterial expression of 5-HT2B and 5-HT1B receptors during development of DOCA-salt hypertension

BMC Pharmacol

Occupancy of agonist drugs at the 5-HT1A receptor

Neuropsychopharmacology

5-HT2A receptor-mediated out-ward current in C6 glioma cells is mimicked by intracellular IP3 release

NeuroReport

5-Hydroxytryptamine type 2A receptors regulate cyclic AMP accumulation in a neuronal cell line by protein kinase C-dependent and calcium/calmodulin-dependent mechanisms

Mol Pharmacol

5-HT2C receptor agonists as potential drugs for the treatment of obesity

Curr Top Med Chem

The haemodynamic effects of ketanserin versus dihydralazine in severe early-onset hypertension in pregnancy

Br J Obstet Gynaecol

The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors

Br J Pharmacol

Blockade of 5-HT(2A) receptors by sarpogrelate protects the heart against myocardial infarction in rats

J Cardiovasc Pharmacol Ther

Comparative desensitization of the human 5-HT2A and 5-HT2C receptors expressed in the human neuro blastoma cell line SH-SY5Y

Br J Pharmacol

Ketanserin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease

Drugs

5-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfon-amide (SB-271046): a potent, selective, and orally bioavailable 5-HT6 receptor antagonist

J Med Chem

Biochemical, electrophysiological and neurohormonal studies with B-20991, a selective 5-HT1A receptor agonist

Pharmacology

Pyrroloquinoxaline derivatives as high-affinity and selective 5-HT(3) receptor agonists: synthesis, further structure-activity relationships, and biological studies

J Med Chem

Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome

J Clin Endocrinol Metab

Chinese hamster serotonin (5HT) type 2 receptor cDNA sequence

Nucleic Acids Res

Review article
Functions of 5-HT_2A receptor and its antagonists in the cardiovascular system

5-Hydroxytryptamine_2A receptor and its antagonists

Signaling pathway of 5-hydroxytryptamine_2A receptor

Molecular aspects of 5-hydroxytryptamine_2A receptors

Clinical significance of 5-hydroxytryptamine_2A receptor and its antagonists

5-HT_4(a) and 5-HT_4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle

5-HT_2A receptor-mediated out-ward current in C6 glioma cells is mimicked by intracellular IP3 release

The pharmacology and distribution of human 5-hydroxytryptamine_2B (5-HT_2B) receptor gene products: comparison with 5-HT_2A and 5-HT_2C receptors

Role of second messengers in agonist up-regulation of 5-HT_2A receptor binding sites in cerebellar granule neurons: involvement of calcium influx and a calmodulin-dependent pathway