5-HT1A modulator 1
目录号 : GC312345-HT1Amodulator1对5HT1A,肾上腺素能α1和多巴胺D2受体具有非常高的亲和力,IC50分别为2±0.3nM,10±3nM和40±9nM。
Cas No.:142477-34-7
Sample solution is provided at 25 µL, 10mM.
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Kinase experiment: | Binding is determined using membranes prepared from bovine hippocampus. The receptor is labeled with 0.5 nM [3H]-8-hydroxydipropylaminotetralin (8-OH-DPAT) by incubation at 25°C for 30 min with 11 concentrations of the test compounds (1-105 nM). Nonspecific binding is determined using 10-5 Mbuspirone. Competition experiments are analyzed using the iterative nonlinear least-squares curve-fitting program Inplot 4, graphpad; IC50 values are calculated using the Cheng-Prusoff equation[1]. |
Animal experiment: | Rats[1]Wistar rats (n=6) are used. 5-HT1A modulator 1 is tested at pharmacological doses (1 and 2 mg/kg ip, respectively) and at high doses (32 and 64 mg/kg ip) in rats. The intensity of forepaw treading is expressed as percentage of the maximal possible score. The 5HT1A agonist 8-OH-DPAT induces forepaw treading and is used as a reference compound. Mice[1] Swiss mice are injected with the test compound (e.g., 5-HT1A modulator 1, 0.25 and 1 mg/kg ip) before an injection of 5HTP (400 mg/kg ip). The number of head twiches occurring in a 10 min period starting 10 min after the injection of 5HTP is counted. Cyproheptadine is used as reference compound. |
References: [1]. Taverne T, et al. Novel benzothiazolin-2-one and benzoxazin-3-one arylpiperazine derivatives with mixed 5HT1A/D2 affinity as potential atypical antipsychotics. J Med Chem. 1998 Jun 4;41(12):2010-8. |
5-HT1A modulator 1 displays very high affinities for the 5HT1A, adrenergic α1 and dopamine D2 receptor with IC50s of 2 ±0.3 nM, 10 ± 3 nM and 40 ±9 nM, respectively.
5-HT1A modulator 1 (Compound 24) also displays affinities for the 5HT1B, 5-HT2A and 5-HT2C receptor with IC50s of 300±55 nM, 500±75 nM, and 4000±440 nM, respectively[1].
5-HT1A modulator 1 (Compound 24) shows clear antagonist action at 5HT2A receptor subtype in mice. The antagonism is nearly complete at the dose of 1 mg/kg ip for 5-HT1A modulator 1 (94% of antagonism, p<0.01). 5-HT1A modulator 1 completely blocks the stereotypies and the climbing at the dose of 1 mg/kg ip (100% of antagonism). 5-HT1A modulator 1 is also tested in rats, using the same paradigm. After oral administration, 5-HT1A modulator 1 significantly (p<0.05) reduces the hyperactivity by 50% at the doses of 2 and 4 mg/kg po, respectively 63% and 58% of antagonism for 5-HT1A modulator 1; the antagonism is complete (103% and 108%) at the respective doses of 8 and 16 mg/kg po for 5-HT1A modulator 1 (p<0.01)[1].
[1]. Taverne T, et al. Novel benzothiazolin-2-one and benzoxazin-3-one arylpiperazine derivatives with mixed 5HT1A/D2 affinity as potential atypical antipsychotics. J Med Chem. 1998 Jun 4;41(12):2010-8.
Cas No. | 142477-34-7 | SDF | |
Canonical SMILES | O=C1SC2=CC(CCN3CCN(C4=CC=CC=C4OC)CC3)=CC=C2N1C | ||
分子式 | C21H25N3O2S | 分子量 | 383.51 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.6075 mL | 13.0375 mL | 26.0749 mL |
5 mM | 0.5215 mL | 2.6075 mL | 5.215 mL |
10 mM | 0.2607 mL | 1.3037 mL | 2.6075 mL |
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Serotonin and brain function: a tale of two receptors
Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.
The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects
Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor-receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor-receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.
[ O-methyl-11C]2-{4-[4-(7-Methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2 H-[1,2,4]triazine-3,5-dione
[O-methyl-11C]2-{4-[4-(7-Methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione ([11C]MPT) is a radioligand developed for positron emission tomography (PET) imaging of serotonin-1A (5-hydroxytryptamine 1A (5-HT1A)) receptors in the central nervous system (1). It is a selective 5-HT1A agonist labeled with 11C, a positron emitter with a physical half-life (t?) of 20.4 min (1, 2).
The 5-HT neurotransmission system comprises mainly neurons in the brainstem, with nerve tracts extending from these neurons to many areas of the brain and spinal cord (3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT1 to 5-HT7), many of which also contain several subtypes (4). There are five receptor subtypes within the G-protein–coupled 5-HT1 receptor family, with the 5-HT1A subtype located primarily in the limbic forebrain (the hippocampus, entorhinal cortex ,septum, and raphe) (4, 5). 5-HT1A receptors appear to function both as presynaptic (somatodendritic) autoreceptors in the raphe nuclei and as postsynaptic receptors in the terminal fields. This receptor subtype is involved in the modulation of emotion and the function of the hypothalamus, and it is implicated in the pathogenesis of anxiety, depression, hallucinogenic behavior, motion sickness, dementia, schizophrenia, and eating disorders (6). A radioligand that can be used to assess the in vivo densities of 5-HT1A receptors and their changes may facilitate investigation of the relationship of these receptors to various neuropsychiatric diseases and aid in the design of novel drugs for their treatment.
Many psychiatric drugs modulate serotonergic transmission or specifically target the 5-HT1A receptors (2). Various compounds have been radiolabeled for visualization and quantification of these receptors (7). 5-HT1A receptors appear to exist in the high (HA) and low (LA) agonist affinity states. Antagonist ligands bind to both the HA and LA conformations, whereas agonist ligands bind to the HA state, which is coupled to G-protein. WAY 100635 was developed as a highly selective, silent antagonist (possessing no intrinsic agonist activity) of 5-HT1A receptors at both pre- and postsynaptic sites. WAY 100635 radiolabeled with 11C at the carbonyl position is an effective radioligand but it is rapidly cleared and metabolized. Analogs of WAY 100635 that bear bulkier cycloalkylcarbonyl groups appear to be more resistant to amide hydrolysis. However, the added lipophilicity also reduces receptor affinity (8). Although 5-HT1A receptor agonist ligands can elicit pharmacologic effects, there are some distinct potential applications of radiolabeled 5-HT1A receptor agonist ligands because they behave like serotonin, which binds preferentially to the HA sites (1, 9). Kumar et al. (1) selected MPT for development as a radiolabeled 5-HT1A receptor agonist probe because of its high affinity (pKi = 10.49) and favorable calculated lipophilicity (clogP = 1.8) (10, 11)
5-HT Receptors and the Development of New Antidepressants
Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression.
5-HT1A receptor as a key player in the brain 5-HT system
Among an impressive variety of identified serotonin receptors, 5-HT1A attracts particular attention due to its central role in the regulation of 5-HT-ergic neurotransmission and the data on its involvement in the mechanisms of stress response, aggressive behavior, anxiety, and depression. This review concentrates on the cross-regulation between 5-HT receptors and the implication of the 5-HT1A receptor in the genetic control of 5-HT-related behavior. Specifically, it describes the (1) functional interactions between 5-HT1A, 5-HT2A, 5-HT3, and 5-HT7 receptors; (2) cross-talk between 5-HT1A receptor and genes encoding key members of the brain 5-HT system; (3) implication of the 5-HT1A receptor in natural hibernation and genetic predisposition to different kinds of defensive behavior; and (4) role of 5-HT1A autoreceptors and heteroreceptors in anxiety, depression, and suicide, and in the antidepressant effect of serotonin reuptake inhibitors. This review provides converging lines of evidence that the 5-HT1A receptor contributes to the action of other 5-HT receptors, modulating their effect on behavior, and describes new data on the unique role of the 5-HT1A receptor in the indirect regulation of gene expression and in the autoregulation of the brain 5-HT system.