5-HT2B Receptors

Neuropharmacology, 1997

SB242084has a high affinity (pKi9.0) for the cloned human 5-HT2Creceptor and 100-and 158fold selectivity over the closely related cloned human 5-HTz~and 5-HT2~subtypesrespectively. SB 242084 had over 100-foldselectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositolhydrolysis using SH-SY5Ycells stably expressing the cloned human 5-HT2Creceptor, SB 242084acted as an antagonistwith a pKbof 9.3, whichclosely resembledits corresponding receptor binding affinity. SB 242084potently inhibited m-chlorophenylpiperazine(mCPP,7 mgkg i.p. 20 min pre-test) -inducedhypolocomotionin rats, a model of in vivocentral 5-HT2Creceptor function, with an ID50of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084(0.1-1mg/kg i.p.) exhibited an anxiolytic-likeprofile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084(0.1-1mg/kg i.p.) also markedlyincreasedpunishedrespondingin a rat Geller-Seifterconflict test of anxiety, but had no consistenteffect on unpunishedresponding.A large acute dose of SB 242084(30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure thresholdtest. Also, while SB 242084(2 and 6 mg/kg p.o. 1 hr pre-test) antagonizedthe hypophagicresponseto mCPP, neither acute nor subchronicadministrationof the drug,for 5 days at 2 or 6 mg/kgp.o. twice daily, affectedfood intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsantor hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2Creceptor. 01997 Elsevier Science Ltd.

European Journal of Pharmacology, 1996

We have evaluated the effects of ligands with varying efficacies at 13-adrenoceptors and 5-HT~A receptors in three in vivo models reflecting pre-and/or postsynaptic 5-HTIA receptor activation. Forepaw treading in rats is mediated by postsynaptic 5-HT)A receptors, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamin)tetralin)-induced discriminative stimulus is predominantly mediated by postsynaptic, but presynaptic 5-HTIA receptors might also be involved, and footshock-induced ultrasonic vocalization involves predominantly presynaptic 5-HT1A receptors. In vitro receptor binding studies demonstrated high 13-adrenoceptor and 5-HT1A receptor affinity of (-)-penbutolol, high 13-adrenoceptor and 60 times lower 5-HTIA receptor affinity of (+)-penbutolol, high 13-adrenoceptor affinity and about 100 times lower 5-HT~A receptor affinity of pindolol and (-)-tertatolol, only affinity for 13-adrenoceptors of metoprolol and ICI 118,551 (erythro-D,L-1-(7-methylindan-4-yloxy)-3-isopropylamine-butan-2-ol, and only affinity for 5-HT)A receptors of WAY 100.635

Life Sciences, 2003

The 5-HT 2A and 5-HT 2C receptors belong to the G-protein-coupled receptor (GPCR) superfamily. GPCRs transduce extracellular signals to the interior of cells through their interaction with G-proteins. The 5-HT 2A and 5-HT 2C receptors mediate effects of a large variety of compounds affecting depression, schizophrenia, anxiety, hallucinations, dysthymia, sleep patterns, feeding behaviour and neuro-endocrine functions. Binding of such compounds to either 5-HT 2 receptor subtype induces processes that regulate receptor sensitivity. In contrast to most other receptors, chronic blockade of 5-HT 2A and 5-HT 2C receptors leads not to an up-but to a (paradoxical) down-regulation. This review deals with published data involving such non-classical regulation of 5-HT 2A and 5-HT 2C receptors obtained from in vivo and in vitro studies. The underlying regulatory processes of the agonistinduced regulation of 5-HT 2A and 5-HT 2C receptors, commonly thought to be desensitization and resensitisation, are discussed. The atypical down-regulation of both 5-HT 2 receptor subtypes by antidepressants, antipsychotics and 5-HT 2 antagonists is reviewed. The possible mechanisms of this paradoxical down-regulation are discussed, and a new hypothesis on possible heterologous regulation of 5-HT 2A receptors is proposed. D

Neurochemical Research, 1991

Progress in the field of neuronal receptor research has accelerated during the last few years due to developments in pharmacology and molecular biology. This is particularly true in the case of the serotonin 5-HTIA receptor. In 1983 the very selective, high affinity 5-HTla agonist 8-OH-DPAT was developed which allowed the pharmacology and distribution of the 5-HT1A receptor in the central nervous system of the rat and man to be extensively characterized. By 1987, the gene encoding this receptor protein was cloned and sequenced, allowing not only elucidation of its structure, but also better insight into the nature of its coupling to transmembrane signal transduction systems. Thus in a short period of time considerable knowledge has accumulated on how serotonin exerts its functions in the central nervous system via the 5-HT1A receptor. In the present review we will briefly discuss some of the latest developments regarding the 5-HT:A receptor.

Neuropharmacology, 1999

It is now nearly 5 years since the last of the currently recognised 5-HT receptors was identified in terms of its cDNA sequence. Over this period, much effort has been directed towards understanding the function attributable to individual 5-HT receptors in the brain. This has been helped, in part, by the synthesis of a number of compounds that selectively interact with individual 5-HT receptor subtypes-although some 5-HT receptors still lack any selective ligands (e.g. 5-ht 1E , 5-ht 5A and 5-ht 5B receptors). The present review provides background information for each 5-HT receptor subtype and subsequently reviews in more detail the functional responses attributed to each receptor in the brain. Clearly this latter area has moved forward in recent years and this progression is likely to continue given the level of interest associated with the actions of 5-HT. This interest is stimulated by the belief that pharmacological manipulation of the central 5-HT system will have therapeutic potential. In support of which, a number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction.

CNS Drug Reviews, 1997

British Journal of Pharmacology, 1999

The releases of [3H]5-hydroxytryptamine ([3H]5-HT) and of endogenous glutamic acid and their modulation through presynaptic h5-HT1B autoreceptors and h5-HT1D heteroreceptors have been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery. The inhibition by 5-HT of the K+ (15 mM)-evoked overflow of [3H]5-HT was antagonized by the 5-HT1B/5-HT1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5-HT1D heteroreceptor regulating glutamate release. The recently proposed selective h5-HT1B receptor ligand SB-224289 also prevented the effect of 5-HT at the autoreceptor, being inactive on its own; in contrast, SB-224289, at 1 microM, was unable to interact with the h5-HT1D heteroreceptor. The inhibitory effect of 5-HT on the K+-evoked overflow of glutamate was antagonized by the h5-HT1D receptor ligand BRL-15572; added in the absence of 5-HT the compound was without effect. BRL-15572 (1 microM) was unable to modify the effect of 5-HT at the autoreceptor regulating [3H]5-HT release. The selective 5-HT1A receptor antagonist (+)-WAY 100135, previously found to be an agonist at the h5-HT1D heteroreceptor regulating glutamate release, could not interact with the h5-HT1B autoreceptor when added at 1 microM. It is concluded that native h5-HT1B and h5-HT1D receptors exhibit a hitherto unexpected pharmacological diversity.

British Journal of Pharmacology, 1994

1 SB 200646A, N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride, the first reported selective 5-HT2C,2B over 5-HT2A receptor antagonist, (pK, rat 5-HT2c receptor 6.9, pA2 rat 5-HT2B receptor 7.5, pK, rat 5-HT2A receptor 5.2) dose-dependently blocked a putative rat model of 5-HT2c receptor activation; 1-(3-chlorophenyl)piperazine (mCPP, 5 mg kg-', i.p. 20 min pretest)-induced hypolocomotion (estimated ID50 19.2mg kg-', p.o.). 2 SB 200646A also blocked another putative in vivo model of 5-HT2c receptor function; mCPP (5 mg kg-', i.p. 20 min pretest)-induced hypophagia in 23 h food-deprived rats (estimated ID5o 18.3 mg kg-', p.o.). 3 SB 200646A did not antagonize 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shakes in rats at doses up to 200mgkg'1, p.o., an effect thought to be mediated by 5-HT2A receptors for which SB 200646A has its next highest affinity (50 fold less) after the 5-HT2c and 5-HT2B sites.

Neuropharmacology, 1997

Sunun ary-RS 576391, by being a partial agonist in rat esophagusbut a competitive antagonistin guinea-pig ileum, is one of several ligands which operationally discriminate among 5-HT4receptors in different tissues. The discovery-of splice variants of the 5-HT4receptor, 5-HT4sand 5-HT4~,raises the possibility that this functional heterogeneity among 5-HT4receptors may be due to differences in the interaction of ligands with differentisoformsof the receptor.To test this idea, the functionaland bindinginteractions of RS 57639with rat 5-HT4sand 5-HTw receptorswere characterized.RS 57639stimulated adenylatecyclase in cells expressing5-HT4s or 5-HT4~receptors with similar potency (pEC~O = 7.9 + 0.1 and 7.6~0.1) and efficacy (71 + 3 and 59~4% of 5-HT).

The Scientific World JOURNAL, 2010

Serotonin 2C receptors are G protein-coupled receptors expressed by GABAergic, glutamatergic, and dopaminergic neurons. Anatomically, they are present in various brain regions, including cortical areas, hippocampus, ventral midbrain, striatum, nucleus accumbens, hypothalamus, and amygdala. A large body of evidence supports a critical role of serotonin 2C receptors in mediating the interaction between serotonergic and dopaminergic systems, which is at the basis of their proposed involvement in the regulation of mood, affective behavior, and memory. In addition, their expression in specific neuronal populations in the hypothalamus would be critical for their role in the regulation of feeding behavior. Modulation of these receptors has therefore been proposed to be of interest in the search for novel pharmacological strategies for the treatment of various pathological conditions, including schizophrenia and mood disorders, as well as obesity. More precisely, blockade of serotonin 2C receptors has been suggested to provide antidepressant and anxiolytic benefit, while stimulation of these receptors may offer therapeutic benefit for the treatment of psychotic symptoms in schizophrenia and obesity. In addition, modulation of serotonin 2C receptors may offer cognitive-enhancing potential, albeit still a matter of debate. In the present review, the most compelling evidence from the literature is presented and tentative hypotheses with respect to existing controversies are outlined.