m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor

Thomas, David R.; Gager, Tracey; Holland, Vicky; Brown, Anthony M.; Wood, Martyn

doi:10.1097/00001756-199606170-00002

Cited by 40 publications

(23 citation statements)

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“…Our findings are in good agreement with previous studies showing mCPP to be a weak partial agonist at the 2B receptor (Baxter et al, 1994;Porter et al, 1999;Rothman et al, 2000;Vickers et al, 2001). Others have observed that mCPP displays no intrinsic agonist activity and acts as an antagonist at the cloned human 5-HT 2B receptor (Thomas et al, 1996;Wood et al, 1997). As a weak partial agonist at the 2B receptor, mCPP may behave as a functional antagonist in some assay systems.…”

Section: Discussionsupporting

confidence: 93%

Pharmacological Evidence for a Functional Serotonin-2B Receptor in a Human Uterine Smooth Muscle Cell Line

Kelly¹,

Sharif²

2006

J Pharmacol Exp Ther

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The present study investigated the serotonin-induced increase in phosphoinositide hydrolysis and mobilization of intracellular Ca 2ϩ ([Ca 2ϩ ] i ) in human uterine smooth muscle cells (HUSMCs) to identify the serotonergic receptor positively coupled to phospholipase C in these cells. In phosphoinositide (PI) assays, serotonin (5-HT) and ␣-methyl-5-HT were potent, full agonists (EC 50 ϭ 20 and 4.1 nM, respectively), whereas the phenyleth- Serotonin (5-hydroxytryptamine, 5-HT) is known to exert a wide variety of physiological actions through its interaction with an extensive family of 5-HT cell surface receptors (Hoyer et al., 1994(Hoyer et al., , 2002. In particular, the 5-HT 2 receptor family comprises three subtypes, 5-HT 2A , 5-HT 2B , and 5-HT 2C , which have been reported to play a major role in a host of central nervous system functions including anxiety, depression, migraine, obesity, and schizophrenia. Due to the involvement of 5-HT 2 receptor signaling in these disorders, there has been an increased interest in the therapeutic potential of selective 5-HT 2 ligands as antidepressants, antiobesity drugs, and anxiolytic agents (Hoyer et al., 1994;. Further studies have identified serotonin in human aqueous humor (Veglio et al., 1998) and functionally coupled 5-HT 2 receptors in rat retinal pigment epithelial cells (Osborne et al., 1993) and bovine ciliary epithelium (Inoue-Matsuhisa et al., 2003).These findings suggested a possible role of serotonin and its receptors in aqueous humor dynamics and as a possible target for ocular pathologies. Indeed, it has recently been shown that topical ocular administration of 5-HT 2 receptor agonists effectively lowered intraocular pressure in a nonhuman primate model of laser-induced ocular hypertension (May et al., 2003), suggesting a potential utility of 5-HT 2 agonists as antiglaucoma therapeutics. However, the current lack of subtype-selective ligands, especially agonists, has made it difficult to ascribe the hypotensive action of these molecules to an individual 5-HT 2 receptor subtype.Recently, the appetite suppressant fenfluramine was withArticle, publication date, and citation information can be found at

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Section: Discussionsupporting

confidence: 93%

Pharmacological Evidence for a Functional Serotonin-2B Receptor in a Human Uterine Smooth Muscle Cell Line

Kelly¹,

Sharif²

2006

J Pharmacol Exp Ther

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“…In contrast, the present binding studies revealed higher binding affinity of BW723C86 at h5-HT 2B sites, but showed comparable potency and efficacy at h5-HT 2B and h5-HT 2C sites in eliciting [ 3 H]PI depletion. Although the present functional selectivities should be interpreted in the context of the marked h5-HT 2C receptor reserve, these data are consistent with the action of BW723C86 in activating PLC at h5-HT 2C expressed in HEK293 cells (Thomas et al 1996;Wood et al 1997).…”

Section: H5-ht 2c Receptors Alkylation With Eedq Reveals Receptor Ressupporting

confidence: 87%

“…Indeed, agonist actions of mCPP have been characterised (Kennett and Curzon 1988;Newton et al 1996;Porter et al 1999;Miller et al 2000;Jerman et al 2001). As concerns actions at recombinant h5-HT 2B and h5-HT 2C receptors, Thomas et al (1996) documented antagonist properties at h5-HT 2B receptors expressed in HEK293 cells. However, these findings may be characteristic of that expression system inasmuch as, in the present CHO cell line (which expresses a similar level of 5-HT 2B receptors), partial agonist properties of mCPP were observed.…”

Section: H5-ht 2c Receptors Alkylation With Eedq Reveals Receptor Resmentioning

confidence: 99%

Characterization of phospholipase C activity at h5-HT 2C compared with h5-HT 2B receptors: influence of novel ligands upon membrane-bound levels of [ 3 H]phosphatidylinositols

Cussac

Newman‐Tancredi

Quentric

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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Employing a novel, rapid and sensitive method for evaluation of phospholipase C (PLC) activity, the present study characterized the actions of diverse agonists and antagonists at human (h)5-HT2C receptors expressed in Chinese Hamster Ovary (CHO) cells. In addition, affinities and efficacies at these sites were compared with those obtained at h5-HT2B receptors.5-HT elicited a robust and rapid reduction in levels of the pre-labelled, membrane-bound substrate of PLC, [3H]phosphatidylinositols ([3H]PI). The time-course of [3H]PI depletion paralleled that of [3H]inositol phosphate ([3H]IP) accumulation, as determined by conventional anion exchange chromatography. Inactivation of h5-HT2C receptors with the alkylating agent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), revealed a large receptor reserve, with half-maximal PLC activation induced by a concentration of 5-HT occupying only 5% of sites. In analogy to 5-HT ( Emax=100%), DOI, MK212 and mCPP, as well as the novel ligands, Ro600332, Ro600175 and BW723C86, showed "full" efficacy at h5-HT2C sites. Their efficacies were similar at h5-HT2B sites, with the exception of mCPP and MK212, which acted as partial agonists. Further, lisuride and Ro600869 behaved as partial agonists and antagonists at h5-HT2C and h5-HT2B receptors, respectively. As concerns functional selectivity (potency for induction of [3H]PI depletion), only Ro600175 preferentially activated h5-HT2B sites. In contrast, Ro600332 preferentially activated h5-HT2C receptors. Amongst antagonists, RS102221 and SB242084 displayed a marked preference for h5-HT2C sites, whereas LY266097, S33526 and SB204741 behaved as selective antagonists at h5-HT2B receptors. At both h5-HT2C and h5-HT2B receptors, antagonist potency (p Kb) and binding affinity (p Ki) were highly correlated. In conclusion, this rapid and innovative method for determination of PLC activity permitted characterization of an extensive range of novel ligands at h5-HT2C receptors. Although several antagonists clearly differentiated h5-HT2C from h5-HT2B receptors under these conditions, highly selective agonists remain to be identified.

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“…m-CPP binds as an agonist at the 5HT1C and 5HT2C (Graeff, 1996), as an antagonist at the 5HT2B (Thomas, Gager, Holland, Brown, & Wood, 1996), and as a partial agonist at the 5HT2A (Willins & Meltzer, 1997) and 5HT3 (Hoyer, Neijt, & Karpf, 1989;Kahn & Wetzler, 1991) receptor sites in the brain. m-CPP may also act at presynaptic serotonin transporter sites in humans (Baumann, Mash, & Staley, 1995).…”

Section: Introductionmentioning

confidence: 99%

Altered response to meta‐chlorophenylpiperazine in anorexia nervosa: Support for a persistent alteration of serotonin activity after short‐term weight restoration

Frank

Kaye

Weltzin

et al. 2001

Intl J Eating Disorders

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m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor

Cited by 40 publications

References 0 publications

Pharmacological Evidence for a Functional Serotonin-2B Receptor in a Human Uterine Smooth Muscle Cell Line

Pharmacological Evidence for a Functional Serotonin-2B Receptor in a Human Uterine Smooth Muscle Cell Line

Characterization of phospholipase C activity at h5-HT 2C compared with h5-HT 2B receptors: influence of novel ligands upon membrane-bound levels of [ 3 H]phosphatidylinositols

Altered response to meta‐chlorophenylpiperazine in anorexia nervosa: Support for a persistent alteration of serotonin activity after short‐term weight restoration

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