Serotonergic drugs and valvular heart disease

Rothman, Richard B.; Baumann, Michael H.

doi:10.1517/14740330902931524

Cited by 127 publications

(94 citation statements)

References 79 publications

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“…This includes d-fenfluramine and sibutramine; both were withdrawn due to cardio-vascular side effects [337]. A likely cause of fenfluramine-induced valvulopathy is activation of 5-HT2B receptors on heart valves by its metabolite norfenfluramine [339,340]. Sibutramine is a 5-HT and noradrenaline re-uptake inhibitor, very similar to some antidepressant drugs.…”

Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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Section: Serotonin and The Pharmacotherapy Of Obesitymentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

View full text Add to dashboard Cite

show abstract

“…One common problem with most existing, selective 5-HT 2C agonists, including lorcaserin, is that they also activate 5-HT 2A and 5-HT 2B receptors at higher concentrations, which can lead to hallucinations (Glennon et al, 1984;Nichols, 2009) and cardiac valvulopathy, respectively (Rothman and Baumann, 2009). Pharmacological and behavioral data obtained using the novel and potent 5-HT 2C -specific agonist (2)-MBP are presented herein.…”

Section: Introductionmentioning

confidence: 99%

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Canal

Morgan

Felsing

et al. 2014

J Pharmacol Exp Ther

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Development of 5-HT 2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT 2C selective agonists also activate 5-HT 2A and/or 5-HT 2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT 2C receptor agonist, (2) 2)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (2)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (2)-MBP, the enantiomer (1)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT 2C receptor-specific agonist, such as (2)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders.

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“…Activation of the receptor on heart valve interstitial cells is believed to result in abnormal deposition of extracellular matrix components, resulting in thickening of valve leaflets, ultimately producing valvular insufficiency or valvulopathy (Fitzgerald et al, 2000;Rothman et al, 2000;Huang et al, 2009;Rothman and Baumann, 2009;Elangbam, 2010;Hutcheson et al, 2011). The appetite suppressant fenfluramine, perhaps the most notorious valvulopathogen, was withdrawn from the US market in 1997.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of 5-HT_2BReceptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration

Unett

Gatlin

Anthony

et al. 2013

J Pharmacol Exp Ther

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The kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptormediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine 2B (5-HT 2B ) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from Ga qmediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signalregulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT 2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptordissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT 2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds.

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Serotonergic drugs and valvular heart disease

Cited by 127 publications

References 79 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Kinetics of 5-HT_2BReceptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration

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Serotonergic drugs and valvular heart disease

Cited by 127 publications

References 79 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

Kinetics of 5-HT2BReceptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration

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A Novel Aminotetralin-Type Serotonin (5-HT)_2CReceptor-Specific Agonist and 5-HT_2ACompetitive Antagonist/5-HT_2BInverse Agonist with Preclinical Efficacy for Psychoses

Kinetics of 5-HT_2BReceptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration