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5-HT Receptors and Their Ligands, Tocris Reviews No 5-HT5-HT Receptors Receptors and and their their Ligands Ligands Figure 1. Structures of some 5-HT uptake Peter J. Pauwels inhibitors Fluoxetine hydrochloride Centre d'Immunologie Pierre Fabre, 5, (Cat. No. 0927) avenue Napoléon III B.P. 497, F-74164 Saint-Julien-en-Genevois Cedex, France Peter Pauwels is Research Director of Centre d’Immunologie Pierre Fabre at Saint-Julien en Citalopram hydrobromide Genevois in France. His research includes (Cat. No. 1427) the molecular pharmacology of 5-HT (Bold text denotes compounds available from Tocris) receptors, in particular the mechanisms governing ligand efficacy and diverse signalling via single receptor subtypes. naturally occurring polymorphic variants, and these could be an additional source of biological variation within the 5-HT system. Introduction Current efforts pursue the identification of either Serotonin (5-hydroxytryptamine, 5-HT) produces efficacious or silent ligands with high selectivity its effects through a variety of membrane-bound for the different receptor subtypes. The issue of receptors. 5-HT and its receptors are found both ligand efficacy is both complex and difficult to in the central and peripheral nervous system improve as we know today that ligands may (CNS/PNS), as well as in a number of non- display a wide spectrum of activities: efficacious neuronal tissues in the gut, cardiovascular to partial agonism, silent neutral antagonism, system and blood. 5-HT has been implicated in partial to efficacious inverse agonism (Table 3), the aetiology of numerous disease states, or in some cases protean agonism.1 Although it including depression, anxiety, social phobia, is well established that different agonists do not schizophrenia, obsessive-compulsive and panic necessarily elicit the same magnitude of disorders; in addition to migraine, hypertension, response, it is less clear whether these agonists pulmonary hypertension, eating disorders, also differentiate between various possible vomiting and irritable bowel syndrome. Except signal transduction pathways.1,2 Such differential for the 5-HT receptor, which is a ligand-gated 3 signallingvia a single receptor subtype is an ion channel, 5-HT receptors belong to the G intriguing issue in molecular pharmacology and protein-coupled receptor (GPCR) superfamily emphasizes that a single receptor target could and, with at least fourteen distinct members, be activated in different ways. Consequently, it represent one of the most complex families of would be possible to obtain agonists with neurotransmitter receptors (Tables 1, 2). Splice properties that are bothquantitatively and variants (5-HT 5-HT , 5-ht 5-HT ) and RNA 3467,, qualitatively distinct. It is anticipated that both edited isoforms (5-HT ) have been described, 2C efficacious and selective receptor probes will whilst there is evidence that amongst the provide tools to advance definition of functional heptahelical 5-HT receptors, homo- and effectsin situ , be it in vitro or in vivo , and, in heterodimerisation (5-HT ) can occur. It 1B,1D addition, lead to more efficacious drug should also be noted that there is emerging treatments with fewer side effects for a variety of evidence that 5-HT receptor subtypes have disorders. Molecular genetic approaches offer a Table 1. Different 5-HT receptor subtypes 5-HT1234567 5-HT 5-HT 5-HT 5-ht 5-ht 5-HT Subtypes 5-HT1A , 5-HT 1B , 5-HT 1D , 5-HT 2A , 5-HT 2B , 5-HT 3A , 5-HT 3B 5-ht 5A , 5-ht 5B 5-ht1E , 5-ht 1F 5-HT 2C ¯ ­­­­ Major signalling cAMP IP3 Ion channel cAMP cAMP? cAMP cAMP pathway Tocris Cookson Ltd., UK Tocris Cookson Inc., USA Tel: + 44 (0)117 916 3333 Tel: (800) 421-3701 Fax: + 44 (0)117 916 3344 Fax: (800) 483-1993 [email protected] [email protected] [email protected] www.tocris.com [email protected] Table 2. Summary of changes in 5-HT The 5-HT1 receptor class receptor nomenclature The 5-HT1 receptor class is comprised of five Old nomenclature New nomenclature receptor subtypes (5-HT1A , 5-HT 1B , 5-HT 1D , Receptor Species 5-ht1E and 5-ht 1F ), which, in humans, share 40- 63% overall sequence identity and couple 5-HT1B Rat preferentially, although not exclusively, to Gi/o a 5-HT1D Human, 5-HT 1B proteins to inhibit cAMP formation. The 5-ht1E guinea pig and 5-ht1F receptors are given a lower case 5-HT1Db All species appellation to denote that endogenous receptors with a physiological role have not yet been 5-HT1Da All species 5-HT 1D found. In contrast, 5-HT1A , 5-HT 1B and 5-HT 1D 5-HT22A All species 5-HT receptors have been demonstrated functionally 5-HTD in a variety of tissues from various species. 5-HT2F All species 5-HT 2B 5-HT1A receptors 5-HT1C All species 5-HT 2C 5-HT1A receptors are distributed largely throughout the CNS. In the raphé nuclei, they a Species equivalent, e.g. r5-HT1B for rodents and h5-HT 1B for are somatodendritic and act as autoreceptors to humans. Taken from Barnes and Sharp (1999) inhibit cell firing; postsynaptic 5-HT receptors Neuropharmacology38 1083.3 1A are present in a number of limbic structures, particularly the hippocampus. Activation of complementary strategy for studying distinct 5-HT1A receptors causes neuronal hyper- 5-HT receptor subtypesvia the generation of polarisation.5 Furthermore, in the gastro- gene-targeted and transgenic lines of mice with intestinal tract, 5-HT1A receptors were identified altered expression of 5-HT receptor genes. 5-HT on the guinea pig myenteric plexus where they is also a substrate for the 5-HT transporter, itself function as inhibitory modulators of fast a target in the treatment of depression and excitatory postsynaptic potentials. 5-HT1A social phobia. The 5-HT transporter is the target receptors have been implicated in the for selective serotonin reuptake inhibitors neuroendocrine regulation of adrenocortico- (SSRIs), such as fluoxetine, paroxetine and trophic hormone (ACTH), but not prolactin citalopram (Figure 1), an important class of secretion.6 It has been established that drugs that emerged during the 20th century. activation of postsynaptic 5-HT1A receptors 5-HT receptors are divided, according to the induces a behavioural syndrome, characterized NC-IUPHAR subcommittee on 5-HT receptors, by flat body posture, reciprocal forepaw treading and head weaving. The spontaneous tail-flick into seven distinct classes (5-HT17 to 5-HT ), largely on the basis of their structural and response has also been attributed to 7,8,9 operational characteristics. The reader is postsynaptic 5-HT1A receptor activation; referred to the following reviews on 5-HT whereas evidence for a presynaptic 5-HT1A receptors (Pauwels, 2000; Barnes and Sharp, (auto)receptor in the hyperphagia response 1999; Hoyeret al , 2002)2,3,4 for further reading appears convincing.10 A decrease in blood and details. The present paper focuses on the 5- pressure and heart rate and increased HT receptor ligands that are available as tools locomotor responses can be induced by central for experimental research. 5-HT1A receptor activation, whilst fluoxetine- induced penile erections can be markedly Figure 2. Structures of some 5-HT1 receptor ligands RU 24969 hemisuccinate (Cat. No. 0912) 8-Hydroxy-DPAT hydrobromide (Cat. No. 0529) SB 216641 hydrochloride (Cat. No. 1242) MDL 72832 hydrochloride Buspirone hydrochloride (Cat. No. 0412) (Cat. No. 0962) BRL 15572 hydrochloride (Cat. No. 1207) BRL 54443 (Cat. No. 1129) SB 224289 hydrochloride (Cat. No. 1221) (Bold text denotes compounds available from Tocris) 2 Table 3. Examples of 5-HT ligands, previously characterised as antagonists, behaving as either a partial agonist, a neutral antagonist or an inverse agonist at 5-HT receptors Receptor subtype Partial agonist Neutral Partial inverse Inverse agonist References antagonist agonist Wild-type h5-HT1A WAY 100635Spiperone, methiothepin 155, 156, 157 Wild-type h5-HT1B GR 125743,GR 55562 , SB 224289 , 148, 158, 159 GR 127935, methiothepin 1-naphthylpiperazine 322 r5-HT2A Cys Lys Chlorpromazine,clozapine , 160 haloperidol, loxapine, risperidone Wild-type r5-HT2C Mianserin, spiperone , 161, 162 mesulergine,ketanserin , clozapine, cyproheptadine 312 r5-HT2C Ser Lys Mianserin, mesulergine 163 Wild-type h5-HT4C ML 10375 109 Wild-type h5-HT7long SB 258719, Risperidone,methiothepin , 164 mesulergine olanzapine, clozapine (Bold text denotes compounds available from Tocris) Taken from Pauwels (2000) Biochem.Pharmacol.60 1743.2 potentiated by combined 5-HT1A/1B receptor significantly larger than any of the other 5-HT blockade.11-14 compounds examined because of its higher 26 intrinsic activity at 5-HT1A receptors. Large- The proposed role of 5-HT1A receptors in amplitude 5-HT1A receptor activation with F modulating anxiety-related behaviours is 13640 has been observed and constitutes a supported by recent studies utilising 5-HT1A novel mechanism of profound, central receptor knockout (KO) mice. These animals analgesia.27 demonstrated increased anxiety in a number of experimental paradigms. The KO animals spent 5-HT1B receptors less time in the open arms of the elevated plus 5-HT1B receptors are expressed in the CNS, maze, the elevated zero maze and the centre of concentrated in the basal ganglia, striatum and an open field, and less time exploring a novel frontal cortex and are thought to serve as object. Moreover, these animals demonstrated terminal autoreceptors. In addition, the receptor decreased baseline immobility in the forced may also act as a terminal heteroreceptor, swimming and tail suspension tests.15,16 controlling the release of other neuro- transmitters, such as acetylcholine, glutamate, 5-HT1A receptor agonists, such as buspirone dopamine, noradrenaline and (Figure 2) or gepirone, are being used or g-aminobutyric acid.28 The receptors are also developed for the treatment of anxiety and found on cerebral arteries and other vascular 17,18 depression. The 5-HT1A receptor antagonist tissues. Peripheral effects have been described, andb -adrenoceptor blocker, pindolol, was such as inhibition of noradrenaline release in the reported to enhance the therapeutic efficacy and vena cava and inhibition of plasma shorten the onset of action of SSRIs when co- extravasation produced by trigeminal ganglion administered in depressed patients.
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