m-Chlorophenylpiperazine decreases food intake in a test meal

Walsh, Annabel; Smith, K. A.; Oldman, A; Williams, Clare; Goodall, Edwin; Cowen, Philip J.

doi:10.1007/bf02244883

Cited by 77 publications

(38 citation statements)

References 11 publications

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“…These enhanced properties would suggest that WAY-163909 will have a low propensity for 5-HT 2A/B receptor-mediated side effects. From the early pharmacological studies demonstrating anorectic effects of mCPP in multiple species (Samanin et al, 1979;Curzon, 1988: Kennett andCurzon, 1991;Walsh et al, 1994;Cowen et al, 1995;Sargent et al, 1997) to more recent data with novel 5-HT 2C agonists that demonstrate effects on both food intake and body weight (Martin et al, 1998;Rosenzweig-Lipson et al, 2000;Welmaker et al, 2000;Vickers et al, 2000Vickers et al, , 2003Hayashi et al, 2004;Sabb et al, 2004), the pharmacological data supporting a role for 5-HT 2C agonists in obesity is compelling. The pharmacological data are supported by studies in mice lacking the 5-HT 2C receptor.…”

Section: Discussionmentioning

confidence: 42%

“…Moreover, these mice are insensitive to the hypophagic effects of the nonselective 5-HT 2 receptor agonist mCPP (Tecott et al, 1995). mCPP, the most widely studied agonist at 5-HT 2C receptors, decreases food intake in several species, including humans (Samanin et al, 1979;Walsh et al, 1994;Cowen et al, 1995;Kennett et al, 1997;Sargent et al, 1997). Studies using 5-HT antagonists that differ in selectivity among the 5-HT receptor subtypes have provided evidence supporting a role for the 5-HT 2C receptor in the regulation of this mCPP response Curzon, 1988, 1991).…”

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confidence: 42%

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WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Anorectic Activity

Dunlop¹,

Sabb²,

Mazandarani³

et al. 2005

J Pharmacol Exp Ther

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The pharmacological profile of WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino [6,7,1hi]indole], a novel 5-hydroxytryptamine (HT) 2C (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [125 I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT 2C receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a K i value of 10.5 Ϯ 1.1 nM. Binding affinities determined for the human 5-HT 2A and 5-HT 2B receptor subtypes were 212 and 485 nM, respectively. In functional studies, WAY-163909 stimulated the mobilization of intracellular calcium in CHO cells stably expressing the human 5-HT 2C receptor with an EC 50 value of 8 nM, and E max relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT 2A receptor subtype (EC 50 Ͼ Ͼ 10 M) and was a 5-HT 2B receptor partial agonist (EC 50 185 nM, E max 40%). WAY-163909 exhibited negligible affinity (Ͻ50% inhibition at 1 M) for other receptor sites examined, including human 5-HT 1A , D2, and D3 receptors, and the 5-HT transporter binding site in rat cortical membranes. WAY-163909 exhibited weak affinity for the human D4 (245 nM) and 5-HT 7 (343 nM) receptor subtypes and the ␣1 binding site in rat cortical membranes (665 nM). WAY-163909 produced a dose-dependent reduction in food intake in normal Sprague-Dawley rats (ED 50 ϭ 2.93 mg/kg), an effect blocked by a 5-HT 2C receptor antagonist but not by a 5-HT 2A or 5-HT 2B receptor antagonist. In addition, WAY-163909 decreased food intake in obese Zucker rats and diet-induced obese mice with ED 50 values of 1.4 and 5.19 mg/kg i.p., respectively, consistent with the potential utility of 5-HT 2C receptor agonists as antiobesity agents.At least 14 distinct 5-HT receptor subtypes have been cloned, and their classification has been based on both sequence similarity and common signal transduction pathways (for review, see Barnes and Sharp, 1999). The 5-HT 2 receptor subfamily currently accommodates three subtypes designated 5-HT 2A , 5-HT 2B , and 5-HT 2C , and these receptors belong to the large family of seven transmembrane domain G protein-coupled receptors. They display high sequence homology with each other and common signal transduction (Baxter et al., 1995), principally via the activation of phospholipase C. Alterations or dysfunction of the 5-HT 2C receptor has been implicated in a variety of conditions, including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia, migraine, and erectile dysfunction (Fozard and Gray, 1989;Kennett and Curzon, 1991;Sanders-Bush Article, publication date, and citation information can be found at

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Section: Discussionmentioning

confidence: 42%

mentioning

confidence: 42%

WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Anorectic Activity

Dunlop¹,

Sabb²,

Mazandarani³

et al. 2005

J Pharmacol Exp Ther

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“…A 30mg oral dose of mCPP was selected, as similar doses have been shown to reduce appetite, and, in some cases, induce nausea and anxiety (Sargent et al 1997;Walsh et al 1994;Cowen et al 1995;Kahn et al 1990). Therefore, a 15mg dose was also used, as this dose is not associated with nausea, but may still affect appetite .…”

Section: Designmentioning

confidence: 46%

Effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine on appetite, food intake and emotional processing in healthy volunteers

et al. 2014

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(250 words)Rationale: The treatment of obesity is an increasing global health priority yet few effective drug treatments are currently available. The discovery of novel anti-obesity therapies could be assisted by the validation of experimental (translational) medicine models in healthy volunteers that assess efficacy and safety at an early stage of drug development. Objectives:To examine the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) in an experimental medicine model assessing both appetite and mood. Methods: Using a between-subjects double blind placebo controlled design, 24 male and 24 female participants were randomly assigned to either placebo, 15mg or 30mg mCPP treatment groups. Lunch was eaten from a Universal Eating Monitor (UEM) that measured eating rate and participants completed the P1vital ® Oxford Emotional Test Battery (ETB) and a series of appetite and mood ratings. Results: mCPP reduced appetite, and in females, enhanced measures of satiation. The drug also enhanced memory for emotional material in the word recall and recognition memory tasks of the ETB. Conclusions: The results provide new insight into the effects of mCPP on appetite, satiety and memory in humans. In addition, our data provide an illustration of the value of measuring changes in appetite and mood in healthy volunteers to determine the potential efficacy and safety of novel anti-obesity drugs.

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“…Fenfluramine (Rogers and Blundell, 1979(Foltin et al, 1996) and dexfenfluramine (Drent et al, 1995), two drugs that act on the serotonin system, but were withdrawn from the market in 1997 because of cardiovascular side effects, also reduce food intake in human studies. meta-Chlorophenylpiperazine, a direct serotonin agonist, reduces food intake by 28% in women and 20% in men (Walsh et al, 1994). Another serotonergic drug, sumatriptan, which acts on the 5-HT 1B/1D receptor, also reduced food intake in human subjects (Boeles et al, 1997).…”

Section: Mechanism Of Actionsupporting

confidence: 39%