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1.
Knight AR Misra A Quirk K Benwell K Revell D Kennett G Bickerdike M 《Naunyn-Schmiedeberg's archives of pharmacology》2004,370(2):114-123
In the present study we compared the affinity of various drugs for the high affinity agonist-preferring binding site of human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors stably expressed in monoclonal mammalian cell lines. To ensure that the agonist-preferring conformation of the receptor was preferentially labelled in competition binding experiments, saturation analysis was conducted using antagonist and agonist radiolabels at each receptor. Antagonist radiolabels ([3H]-ketanserin for 5-HT2A receptor and [3H]-mesulergine for 5-HT2B and 5-HT2C receptor) bound to a larger population of receptors in each preparation than the corresponding agonist radiolabel ([125I]-DOI for 5-HT2A receptor binding and [3H]-5-HT for 5-HT2B and 5-HT2C receptor binding). Competition experiments were subsequently conducted against appropriate concentrations of the agonist radiolabels bound to the agonist-preferring subset of receptors in each preparation. These studies confirmed that there are a number of highly selective antagonists available to investigate 5-HT2 receptor subtype function (for example, MDL 100907, RS-127445 and RS-102221 for 5-HT2A, 5-HT2B and 5-HT2C receptors respectively). There remains, however, a lack of highly selective agonists. (–)DOI is potent and moderately selective for 5-HT2A receptors, BW723C86 has poor selectivity for human 5-HT2B receptors, while Org 37684 and VER-3323 display some selectivity for the 5-HT2C receptor. We report for the first time in a single study, the selectivity of numerous serotonergic drugs for 5-HT2 receptors from the same species, in mammalian cell lines and using, exclusively, agonist radiolabels. The results indicate the importance of defining the selectivity of pharmacological tools, which may have been over-estimated in the past, and highlights the need to find more selective agonists to investigate 5-HT2 receptor pharmacology. 相似文献
2.
Brattelid T Kvingedal AM Krobert KA Andressen KW Bach T Hystad ME Kaumann AJ Levy FO 《Naunyn-Schmiedeberg's archives of pharmacology》2004,369(6):616-628
5-HT4 receptor pre-mRNA is alternatively spliced in human (h) tissue to produce several splice variants, called 5-HT4(a) to 5-HT4(h) and 5-HT4(n). Polymerase chain reaction (PCR) with primers designed to amplify both 5-HT4(a) and 5-HT4(b) amplified three additional bands in different tissues, two representing different mRNA species both encoding 5-HT4(g) and one representing mRNA for a novel splice variant named 5-HT4(i), cloned from testis and pancreas respectively. Primary and nested PCR detected both 5-HT4(g) and 5-HT4(i) in multiple tissues. Whereas 5-HT4(i), was found in all cardiovascular tissues analysed, 5-HT4(g) was mainly present in atria. However, quantitative RT-PCR indicated 5-HT4(g) expression also in cardiac ventricle. The pharmacological profiles and ability to activate adenylyl cyclase (AC) were compared between four recombinant h5-HT4 splice variants (a, b, g and i) expressed transiently and stably in HEK293 cells. Displacement of [3H]GR113808 with ten ligands revealed identical pharmacological profiles (affinity rank order: GR125487, SB207710, GR113808>SB203186>serotonin, cisapride, tropisetron>renzapride, 5-MeOT>5-CT). In transiently transfected HEK293 cells cisapride was a partial agonist compared to serotonin at 5-HT4(b), 5-HT4(g) and 5-HT4(i) receptors. In membranes from HEK293 cells stably expressing 5-HT4(g) (3,000 fmol/mg protein) or 5-HT4(i) (500 fmol/mg protein), serotonin and 5-MeOT were full agonists while cisapride was full agonist at 5-HT4(g) and partial agonist at 5-HT4(i), probably due to different receptor expression levels. At both 5-HT4(g) and 5-HT4(i), the behaviour of 5-HT4 receptor antagonists was dependent on receptor level. At high receptor levels, tropisetron and SB207710 and to a variable extent SB203186 and GR113808 displayed some partial agonist activity, whereas GR125487 and SB207266 reduced the AC activity below basal, indicating both receptors to be constitutively active. We conclude that the novel 5-HT4(i) receptor splice variant is pharmacologically indistinguishable from other 5-HT4 splice variants and that the 5-HT4(i) C-terminal tail does not influence coupling to AC. 相似文献
3.
Philippe Schoeffter Daniel Hoyer 《Naunyn-Schmiedeberg's archives of pharmacology》1989,339(6):675-683
Summary The effects of several putative 5-HT1 receptorsubtype selective ligands were investigated in biochemical models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(mtrifluoromethylphenyl)piperazine), mCPP (1-m-chlorophe-nyl)piperazine, 1 CGS 12066 (7-trifluoromethyl-4-(4-methyl1-piperazinyl)-pyrrolo[1,2-a]quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine). Among reported 5-HT1B receptor selective drugs, TFMPP had similar potency at 5HT1A, 5-HT1B and 5-HT1C receptors, mCPP did not separate between 5-HT1B and 5-HT1C receptors, CGS 12066 was equipotent at 5-HT1B and 5-HT1D receptors, and isamoltane was only slightly 5-HTIB versus 5-HT1A selective. Quipazine showed equal potency at 5-HTIB and 5-HT1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT1A receptor selective, was equally potent at 5-HT1A and 5-HT1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT1 receptor subtype. Of interest were the properties of several of these drugs, which behaved as agonists at some receptors and as antagonists at others (e. g. quipazine, 1-NP, PAPP and isamoltane).
Send offprint requests to D. Hoyer at the above address 相似文献
4.
Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders 总被引:4,自引:0,他引:4
Rationale Current treatments for schizophrenia adequately treat the positive symptoms of schizophrenia but only modestly improve cognitive deficits. This review provides evidence for and against the use of selective 5-HT receptor drugs as cognition enhancing agents for schizophrenia and other disorders.Methods Pre-clinical and clinical literature concerned with the role of the serotonergic system in cognition and memory as it relates to schizophrenia is reviewed. Individual 5-HT receptor subtypes for which selective drugs are available that are likely to improve cognition are reviewed. Recommendations for clinical testing are proposed.Results and conclusions Four 5-HT receptor systems (5-HT1A, 5-HT2A, 5-HT4, 5-HT6) are highlighted as suitable targets for enhancing cognition and memory. Because many clinically available antipsychotic drugs already target 5-HT1A, 5-HT2A and 5-HT6 receptors, design of clinical trials will need to take into account the serotonergic pharmacology of concurrently administered antipsychotic medications. 5-HT1A partial agonists and 5-HT2A antagonists have shown modest effectiveness in improving cognition in schizophrenia. 5-HT6-selective compounds for cognition enhancement are in late-stage clinical trials, while 5-HT4 compounds have not yet been tested in humans for cognition enhancement.Recommendations For stand-alone therapy for enhancing cognition, 5-HT1A partial agonists, 5-HT2A antagonists, 5-HT4 partial agonists and 5-HT6 antagonists are all likely to induce at least modest improvement in cognition in schizophrenia. If add-on therapy is contemplated, antipsychotic drugs with weak affinities for serotonin receptors should be used to avoid confounds. It is likely that serotonergic drugs will soon be available as cognition enhancing medications for disorders other than schizophrenia (e.g. dementia). 相似文献
5.
双重作用的多巴胺D2/5-HT2A受体拮抗剂比较药效团分析 总被引:1,自引:0,他引:1
双重作用的多巴胺D2/5-HT2A受体拮抗剂是开发非典型抗精神病药物的有效途径,但最新研究显示, 非典型抗精神病药物将显著增加患者因心律失常及其他心脏疾病而猝死的风险,本文对D2/5-HT2A受体拮抗剂的药效团模型以及可能引起心血管风险的α1A肾上腺素受体拮抗剂和hERG K+通道阻断剂的药效团模型进行比较分析,从药效团模型的角度分析多靶点药物的设计。 相似文献
6.
Four non-selective 5-HT2C/5-HT2A receptor antagonists, mianserin (2–8 mg/kg), 1-naphthyl piperazine (1-NP) (0.5–1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT2A receptor antagonists ketanserin (0.2–1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT1A, 5-HT1B and-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT1D receptor partial agonist and
2 adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H1 receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT2C/5-HT2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT2C/5-HT2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT2C receptor, although the possibility of 5-HT2B receptor mediation is discussed. 相似文献
7.
《Expert opinion on investigational drugs》2013,22(9):1211-1223
Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia. 相似文献
8.
Twenty years ago, we started the characterization of a 5-HT receptor coupled to cAMP production in neurons. This receptor obviously had a different pharmacology to the other 5-HT receptors described at that time, i.e. the 5-HT1, 5-HT2, 5-HT3 receptors. We proposed to name it the 5-HT4 receptor. Nowadays, 5-HT4 receptors are one of the most studied GPCRs belonging to the “rhodopsin” family. Thanks to the existence of a great variety of ligands with inverse agonist, partial agonist, agonist and antagonist profiles, the pharmacological and physiological properties of this receptor are beginning to emerge. Although some 5-HT4 partial agonists have been on the market for gastro-intestinal pathologies, 5-HT4 receptor drugs have still to be commercialized for brain disorders. However, since 5-HT4 receptors have recognized effects on memory, depression and feeding in animal models, there is still hope for a therapeutic destiny of this interesting target in brain disorders. 相似文献
9.
Atheir I. Abbas Peter B. Hedlund Xi-Ping Huang Thuy B. Tran Herbert Y. Meltzer Bryan L. Roth 《Psychopharmacology》2009,205(1):119-128
Rationale Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating
dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients
with major depression in many clinical trials. In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal
event responsible for mediating its antidepressant and antipsychotic properties.
Objectives The purpose of these studies was to determine if amisulpride’s antidepressant actions are mediated by off-target interactions
with other receptors.
Materials and Methods We performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of central nervous
system (CNS) molecular targets and, (2) after finding high potency antagonist affinity for human 5-HT7a serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT7 receptor knockout mice.
Results We discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant
actions in vivo. Significantly, and in contrast to their wild-type littermates, 5-HT7 receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression, the tail suspension
test and the forced swim test.
Conclusions These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride. 相似文献
10.
《Expert opinion on drug safety》2013,12(2):313-327
A growing body of evidence implicates abnormal serotonergic regulation of gastrointestinal function in the pathogenesis of the irritable bowel syndrome (IBS). Drugs targeting this system are therefore attractive concepts. The partial 5-HT4 receptor agonist tegaserod might be predicted to have positive therapeutic effects on a constipated and uncomfortable gut. However, IBS runs a chronic, benign course and carries no associated mortality, so it is imperative that the safety profile of new pharmacological agents made available to physicians is exemplary. The authors review the evidence for 5-HT in the aetiology of IBS and its symptoms, and the data available concerning the partial 5-HT4 receptor agonist tegaserod, in terms of rationale, efficacy and safety. 相似文献
11.
Inçi Sahin-Erdemli Philippe Schoeffter Daniel Hoyer 《Naunyn-Schmiedeberg's archives of pharmacology》1991,344(2):137-142
Summary The effects of several antagonists, known to interact with 5-HT2 receptors (ritanserin, LY 53857, ICI 169,369, methysergide, mesulergine and ketanserin), were tested against 5-HT-stimulated production of inositol phosphate in pig choroid plexus, a 5-HT1C receptor model. These antagonists produced dextral shifts of the concentration response curve to 5-HT in a parallel manner, without depressing significantly the maximal response. The following pA2 values (in parentheses) were obtained: mesulergine (8.88), methysergide (8.85), LY 53857 (8.69), ritanserin (8.69), ICI 169,369 (7.86), and ketanserin (6.57). These pA2 values were in good agreement with the pKD values determined in radioligand binding studies performed in pig choroid plexus with [3H]mesulergine. The present data demonstrate that several drugs described as 5-HT2 receptor selective antagonists (e.g. ritanserin, LY 53857 and ICI 169,369) are also potent, competitive and surmountable antagonists at 5-HT1C receptors. Thus, the results provide further evidence for the pharmacological similarity of 5-HT1C and 5-HT2 receptors. However, in contrast to the situation described with methysergide, ritanserin and LY 53857 in several 5-HT2 receptor models, none of these antagonists acted in a non-competitive or unsurmountable fashion at 5-HT1C receptors. These results suggest, but do not firmly rule out, that at least in the presence of the drugs tested in the present study, 5-HT1C receptors in the choroid plexus do not undergo an allosteric modulation; these findings are apparently in contrast to a model proposed previously for 5-HT2 receptors (Kaumann and Frenken 1985, Naunyn-Schmiedeberg's Arch Pharmacol 328: 295–300)
Send offprint requests to P. Schoeffter at the above address 相似文献
12.
Paul J. Fletcher Maria Tampakeras Abdelmalik Slassi Methvin Isaac Guy A. Higgins 《Neuropharmacology》2009,57(3):259-267
5-HT2C receptor agonists have considerable therapeutic potential, however there is little in vivo data to compare the potency and selectivity of 5-HT2C receptor agonists. Since 5-HT2C receptor agonists reduce locomotor activity and food intake, changes in these drug-induced behaviours in 5-HT2C receptor knockout mice could provide a means to examine receptor selectivity in-vivo. Initially this study compared older 5-HT2C agonists mCPP and MK212, to newer, apparently more selective compounds: Ro 60-0175, WAY161503, CP809,101 and lorcaserin (APD356) on motor activity in wild-type, and 5-HT2C receptor knockout mice. Two 5-HT2C receptor antagonists SB242084 and SDZ SER 082 were also examined. mCPP did not significantly alter activity in wild-type mice, but enhanced activity in knockout animals. MK212 (3 and 10 mg/kg) and Ro 60-0175 (1 and 3 mg/kg) reduced activity in wild-type but not knockout animals. At 10 mg/kg, Ro 60-0175 reduced activity in knockout animals, suggesting loss of 5-HT2C receptor selectivity. CP809,101 and lorcaserin reduced activity in wild-type but not knockout mice. In subsequent feeding studies, Ro 60-0175 and lorcaserin reduced food intake in wild-type animals only. Selectivity of effect for mCPP was marginal. The antagonist SB242084 increased activity in wild-type animals but not in knockout mice; SB242084 did not alter feeding in either genotype. SDZ SER 082 reduced activity in both genotypes implying poor selectivity for 5-HT2C receptors. The data demonstrate that studying food intake, and particularly motor behaviour, in the 5-HT2C receptor knockout mouse is a useful and relatively simple approach for screening 5-HT2C receptor ligands in vivo. 相似文献
13.
The serotonin 5-HT2A receptor (5-HT2AR) and dopamine D2 receptor (D2R) are high-affinity G protein-coupled receptor targets for two different classes of antipsychotic drugs used to treat schizophrenia. Interestingly, the antipsychotic effects are not based on the regulation of same signaling mediators since activation of the 5-HT2AR and of the D2R regulate Gq/11 protein and Gi/o protein, respectively. Here we use radioligand binding and second messenger production assays to provide evidence for a functional crosstalk between 5-HT2AR and D2R in brain and in HEK293 cells. D2R activation increases the hallucinogenic agonist affinity for 5-HT2AR and decreases the 5-HT2AR induced inositol phosphate production. In vivo, 5-HT2AR expression is necessary for the full effects of D2R antagonist on MK-801-induced locomotor activity. Co-immunoprecipitation studies show that the two receptors can physically interact in HEK293 cells and raise the possibility that a receptor heterocomplex mediates the crosstalk observed. The existence of this 5-HT2AR-D2R heteromer and crosstalk may have implications for diseases involving alterations of serotonin and dopamine systems and for the development of new classes of therapeutic drugs. 相似文献
14.
Amy S Newman Nikolaos Batis Gillian Grafton Francesca Caputo Catherine A Brady Jeremy J Lambert John A Peters John Gordon Keith L Brain Andrew D Powell Nicholas M Barnes 《British journal of pharmacology》2013,169(6):1228-1238
Background and Purpose
The 5-HT3 receptor is a ligand-gated ion channel that is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics. However the positive allosteric modulators (PAMs) identified to date have low affinity, which hinders investigation because of non-selective effects at pharmacologically active concentrations. The present study identifies 5-chloroindole (Cl-indole) as a potent PAM of the 5-HT3 receptor.Experimental Approach
5-HT3 receptor function was assessed by the increase in intracellular calcium and single-cell electrophysiological recordings in HEK293 cells stably expressing the h5-HT3A receptor and also the mouse native 5-HT3 receptor that increases neuronal contraction of bladder smooth muscle.Key Results
Cl-indole (1–100 μM) potentiated agonist (5-HT) and particularly partial agonist [(S)-zacopride, DDP733, RR210, quipazine, dopamine, 2-methyl-5-HT, SR57227A, meta chlorophenyl biguanide] induced h5-HT3A receptor-mediated responses. This effect of Cl-indole was also apparent at the mouse native 5-HT3 receptor. Radioligand-binding studies identified that Cl-indole induced a small (∼twofold) increase in the apparent affinity of 5-HT for the h5-HT3A receptor, whereas there was no effect upon the affinity of the antagonist, tropisetron. Cl-indole was able to reactivate desensitized 5-HT3 receptors. In contrast to its effect on the 5-HT3 receptor, Cl-indole did not alter human nicotinic α7 receptor responses.Conclusions and Implications
The present study identifies Cl-indole as a relatively potent and selective PAM of the 5-HT3 receptor; such compounds will aid investigation of the molecular basis for allosteric modulation of the 5-HT3 receptor and may assist the discovery of novel therapeutic drugs targeting this receptor.Linked Articles
Recent reviews on allosteric modulation can be found at:Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476-5381.2012.02223.xRoche D, Gil D and Giraldo J (2013). Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models. British Journal of Pharmacology 169: 1189–1202. doi: 10.1111/bph.12231 相似文献15.
Rationale and objectives WAY-100635 is a prototypical 5-HT1A receptor antagonist and has been used widely as a pharmacological probe to investigate the distribution and function of 5-HT1A receptors. Results from our studies suggested that WAY-100635 was potently inducing effects unrelated to its 5-HT1A receptor affinity. In the present work, we evaluated the in vitro pharmacology of this compound at two D2-like receptor subtypes.Method The functional properties and binding affinities of WAY-100635 were evaluated in HEK 293 cells stably expressing dopamine D2L or D4.4 receptors.Results Initial screens performed by the NIMH Psychoactive Drug Screening Program indicated that WAY-100635 displayed 940, 370, and 16 nM binding affinities at D2L, D3, and D4.2 receptors, respectively. Subsequent saturation analyses demonstrated that the K
d of [3H]WAY-100635 at D4.2 receptors was 2.4 nM, only tenfold higher than 5-HT1A. WAY-100635 and its major metabolite, WAY-100634, were potent agonists in HEK-D4.4 cells (EC50=9.7±2.2 and 0.65±0.2 nM, respectively). WAY-100635 behaved as a full agonist, and WAY-100634 was a nearly full agonist. In HEK-D2L cells, WAY-100635 weakly antagonized the effects of 300 nM quinpirole. Subsequent radioligand binding studies confirmed that WAY-100635 possesses high affinity for D4.4 receptors but binds weakly to D2L receptors (3.3±0.6 and 420±11 nM, respectively).Conclusions This study demonstrates that WAY-100635 is not a “selective” 5-HT1A receptor antagonist, as previously reported, and conclusions drawn from studies that employed WAY-100635 as a selective 5-HT1A antagonist may need to be reevaluated. 相似文献
16.
A. Dumuis H. Gozlan M. Sebben H. Ansanay C. A. Rizzi M. Turconi E. Monferini E. Giraldo P. Schiantarelli H. Ladinsky J. Bockaert 《Naunyn-Schmiedeberg's archives of pharmacology》1992,345(3):264-269
Summary Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3–5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 g/kg, i.v.). No significant binding (Ki>10 mol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic 1, 2, dopaminergic D1, D2 or muscarinic M1–M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.
Send offprint requests to A. Dumuis at the above address 相似文献
17.
Pamela A. Pierce Joanne Y. Kim Stephen J. Peroutka 《Naunyn-Schmiedeberg's archives of pharmacology》1992,346(1):4-11
Summary A molecular structural criterion of ligand selectivity for the 5-HT2 versus 5-HT1C receptor was hypothesized on the basis of radioligand binding data. Despite the large number of compounds which have been tested at both receptors, analysis of published data led to the identification of only five agents which are greater than 10-fold selective for the 5-HT2 versus the 5-HT1C receptor. Comparison of the two-dimensional structures revealed that, although these five compounds represent three distinct structural classes, they share a common structural feature located in the region hypothesized to be involved in receptor binding: a carbonyl or carboxyl oxygen interposed spatially between an aromatic ring and nitrogen atom. This structural feature was used to predict the relative selectivity of compounds that had not previously been analyzed at both the 5-HT2 and 5-HT1C receptors.All six drugs tested which contain the identified reactive carbonyl or carboxyl group were found to be selective for the 5-HT2 versus the 5-HT1C receptor with selectivity ratios ranging from 26 to 380. By contrast, three agents which are structurally similar but do not contain the reactive carbonyl or carboxyl group displayed equally high affinity for both receptor binding sites. Since the physiological roles of the 5-HT2 and 5-HT1C receptor are markedly different, it would be of potential clinical and scientific value to utilize this molecular structural feature to further identify chemical compounds which would selectively interact with only one of the two receptors.
Send offprint requests to S. J. Peroutka at the current address 相似文献
18.
A Morán M M Fernández C Velasco M L Martín L San Román 《British journal of pharmacology》1998,123(6):1205-1213
- A study was made of the effects of 5-carboxamidotryptamine (5-CT) on pressor responses induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Sympathetic stimulation (0.1, 0.5, 1 and 5 Hz) resulted in frequency-dependent increases in blood pressure. Intravenous infusion of 5-CT at doses of 0.01, 0.1 and 1 μg kg−1 min−1 reduced the pressor effects obtained by electrical stimulation. The inhibitory effect of 5-CT was significantly more pronounced at lower frequencies of stimulation. In the present study we characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-CT.
- The inhibition induced by 0.01 μg kg−1 min−1 of 5-CT on sympathetically-induced pressor responses was partially blocked after i.v. treatment with methiothepin (10 μg kg−1), WAY-100,635 (100 μg kg−1) or GR127935T (250 μg kg−1), but was not affected by cyanopindolol (100 μg kg−1).
- The selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT1B/1D receptor agonists sumatriptan and L-694,247 inhibited the pressor response, whereas the 5-HT1B receptor agonists CGS-12066B and CP-93,129 and the 5-HT2C receptor agonist m-CPP did not modify the pressor symapthetic responses.
- The selective 5-HT1A receptor antagonist WAY-100,635 (100 μg kg−1) blocked the inhibition induced by 8-OH-DPAT and the selective 5-HT1B/1D receptor antagonist GR127935T (250 μg kg−1) abolished the inhibition induced either by L-694,247 or sumatriptan.
- None of the 5-HT receptor agonists used in our experiments modified the pressor responses induced by exogenous noradrenaline (NA).
- These results suggest that the presynaptic inhibitory action of 5-CT on the electrically-induced pressor response is mediated by both r-5-HT1D and 5-HT1A receptors.
19.
《Expert opinion on therapeutic patents》2013,23(11):1429-1455
Importance of the field: The 5-HT2C receptor is a GPCR and is one of the 14 subtypes that constitute the serotonin receptor family. The 5-HT2C receptor is exclusively expressed in the CNS where it demonstrates a wide distribution and displays high-affinity interactions with a wide variety of psychiatric medications. Modulators of 5-HT2C have been implicated as a potential treatment for diseases of significant unmet medical need, including obesity, schizophrenia, depression, anxiety, Parkinson's disease, drug addiction, erectile dysfunction and urinary incontinence. Thus, there is a great interest in developing potent and selective 5-HT2C receptor modulators.Areas covered in this review: This review article highlights the research progress in 5-HT2C receptor modulators published in the patent literature between January 2003 and June 2010, giving emphasis to the medicinal chemist's standpoint.What the reader will gain: Readers will rapidly gain an overview of the various 5-HT2C receptor modulators reported in the patent literature in the past 8 years. Furthermore, the readers will learn which structure type can interact with the 5-HT2C receptor. In addition, the readers will be aware of the pharmaceutical companies that have been the main players in the field.Take home message: There is substantial evidence supporting the concept that a selective 5-HT2C receptor modulator should provide benefit in the treatment of a variety of CNS disorders. Although research efforts have identified several promising 5-HT2C receptor modulators that display high functional selectivity, further clinical efficacy and safety data are needed to prove their actual clinical utility. Therefore, the query for selectively acting 5-HT2C receptor modulators is still ongoing. 相似文献
20.
The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT1 receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT1A drugs in conflict procedures. Although chronic administration of 5-HT1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT2 and, perhaps, 5-HT3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT1C/2 and 5-HT3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs. The growing evidence suggesting an interaction between 5-HT receptor types, particularly between 5-HT1A and 5-HT1C/2 receptors, is reviewed, since drugs with these combined properties appear to be particularly efficacious in animal models of anxiety and warrant further detailed analyses. The development of drugs targeted specifically at multiple receptors may provide distinct therapeutic advantages for disorders such as anxiety and depression that appear to involve multiple neurotransmitter systems. 相似文献