GR 125743
目录号 : GC61464
GR125743是一种选择性的5-HT1B/1D受体拮抗剂，与野生型的人h5-HT1B和5-HT1D结合的pKi分别为8.85和8.31。GR125743可用于帕金森病和心血管疾病的研究。
Cas No.:148547-33-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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- Datasheet
GR 125743 is a selective 5-HT1B/1D receptor antagonist, with pKis of 8.85 and 8.31 for wild-type h5-HT1B and wild-type h5-HT1D, respectively. GR 125743 is used for the research of Parkinson's disease and cardiovascular diseases[1][2].
GR 125743 has a Kd of 0.61 nM for h5-HT1B[1].
GR 125743 (0.3 mg/kg; i.p.) produces significant decreases in extracellular 5-HT in the frontal cortex of the conscious guinea pig[2]. Animal Model: Male Dunkin Hartley guinea-pigs (350-450 g)[2]
[1]. T Wurch, et al. Induction of a high-affinity ketanserin binding site at the 5-Hydroxytryptamine(1B) receptor by modification of its carboxy-terminal intracellular portion. Characterization of human serotonin 1D and 1B receptors using [3H]-GR-125743, a novel radiolabelled serotonin 5HT1D/1B receptor antagonist. Biochem Pharmacol. 2000 May 1;59(9):1117-21. [2]. Roberts, C., et al. The role of 5-HT1B/1D receptors in the modulation of 5-hydroxytryptamine levels in the frontal cortex of the conscious guinea pig. European Journal of Pharmacology. 1997 May 12;326(1):23-30.
| Cas No. | 148547-33-5 | SDF | |
| Canonical SMILES | O=C(C1=CC=C(C(C)=C1)C2=CC=NC=C2)NC3=CC=C(C(N4CCN(CC4)C)=C3)OC | ||
| 分子式 | C25H28N4O2 | 分子量 | 416.52 |
| 溶解度 | DMSO: 100 mg/mL (240.08 mM) | 储存条件 | 4°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4008 mL | 12.0042 mL | 24.0085 mL |
| 5 mM | 0.4802 mL | 2.4008 mL | 4.8017 mL |
| 10 mM | 0.2401 mL | 1.2004 mL | 2.4008 mL |
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每只动物给药体积 | ul | |
动物数量 | 只 |
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5-HT 1B/D receptor antagonists
Gen Pharmacol 1997 Sep;29(3):293-303.PMID:9378233DOI:10.1016/s0306-3623(96)00460-0.
1. 5-Hydroxytryptamine-1B (5-HT 1B, formerly designated 5-HT 1D beta) and 5-hydroxy-tryptamine-1D (5-HT 1D, formerly designated 5-HT 1D alpha) receptors are distinct molecular entities that mediate serotonergic neurotransmission. Both are G-protein-coupled receptors without introns in their coding region, negatively coupled to adenylate cyclase; their precise function in human beings remains to be defined. In brain, they are highly enriched in the globus pallidus and the substantia nigra. 2. Presynaptic 5-HT 1B/D receptors take part in the control of the release not only of 5-HT itself, but also of other neurotransmitters-for example, acetylcholine, glutamate, dopamine, noradrenaline and gamma-aminobutyric acid. Selective blockade of central 5-HT 1B/D autoreceptors should facilitate 5-HT neurotransmission and may offer a novel approach to antidepressant therapy. Other 5-HT 1B/D receptors are located postsynaptically; those receptors may be supersensitive in the pathophysiology of obsessive-compulsive disorder and may be a potential target for its treatment. 3. Few if any ligands show selectivity for 5-HT 1B or 5-HT 1D receptors or both. Most pharmacological studies have been performed with nonselective antagonists-for example, metergoline, I-naphthylpiperazine, methiothepin, ketanserin and ritanserin. Recently, a novel series of benzanilides have been reported as the first examples of selective 5-HT 1B/D receptor antagonists. GR 127935, a representative compound of this series, displays mixed agonist-antagonist properties both in vitro and in vivo. It induces upon systemic administration in the guinea pig either an opposite (decrease) effect or a small increase (65%, 5 mg/kg) in the concentration of cortical extracellular 5-HT compared with fluoxetine (218%, 10 mg/kg). The importance of blockade of 5-HT 1B/D receptors in the raphé region, their possible interaction with 5-HT 1A receptors, and consequent inhibition of 5-HT release in terminal 5-HT 1B/D receptor-containing regions are discussed. 4. To find out whether the available so-called 5-HT 1B/D receptor antagonists are indeed antagonists and not partial agonists, efficacy was measured at recombinant human 5-HT 1B and 5-HT 1D receptor sites by using a [35S]-GTP gamma S binding assay to membrane preparations of stably transfected rat C6-glial cell lines. Metergoline and the selective 5-HT 1B/D receptor ligands GR 127935 as well as GR 125743 showed significant intrinsic activity (43% to 69%) at the 5-HT 1D receptor subtype, whereas the nonselective ligand 1-naphthylpiperazine yielded less (15% to 19%) intrinsic activity at both receptor subtypes. In contrast, the nonselective ligands methiothepin, ketanserin and ritanserin are inverse agonists because they displayed negative efficacy (-14% to -28%). Differential blockade of 5-HT 1B/D receptors by neutral antagonists and inverse agonists is discussed in relation to the 5-HT tone on 5-HT 1B/D receptors. 5. It can concluded that 5-HT 1B/D receptor ligands modulate 5-HT neurotransmission through a terminal 5-HT 1B/D receptor. Future work should be directed toward the identification of selective 5-HT 1B and 5-HT 1D receptor ligands that display either neutral antagonist or inverse agonist properties to evaluate the therapeutic potential of 5-HT 1B/D receptor blockade.
Autoradiographic mapping of 5-HT(1B) and 5-HT(1D) receptors in the post mortem human brain using [(3)H]GR 125743
Brain Res 2001 Oct 5;915(1):47-57.PMID:11578619DOI:10.1016/s0006-8993(01)02823-2.
The distribution of 5-HT(1B) and 5-HT(1D) receptors in the human post mortem brain was examined using whole hemisphere autoradiography and the radioligand [(3)H]GR 125743. [(3)H]GR 125743 binding was highest in the substantia nigra and the globus pallidus. Lower levels were detected in the striatum, with the highest densities in the ventromedial parts. In the amygdala, the hippocampus, the septal region and the hypothalamus, lower [(3)H]GR 125743 binding was observed, reflecting low densities of 5-HT(1B/1D) receptors. In the cerebral cortex, binding was similar in most regions, although restricted parts of the medial occipital cortex were markedly more densely labeled. Binding densities were very low in the cerebellar cortex and in the thalamus. Two methods were used to distinguish between the two receptor subtypes, the first using ketanserin to block 5-HT(1D) receptors and the second using SB 224289 to inhibit 5-HT(1B) receptor binding. The autoradiograms indicated that in the human brain, the 5-HT(1B) receptor is much more abundant than the 5-HT(1D) receptor, which seemed to occur only in low amounts mainly in the ventral pallidum. Although [(3)H]GR 125743 is a suitable radioligand to examine the distribution of 5-HT(1B) receptors in the human brain in vitro, the selectivities of ketanserin and SB 224289 are not sufficiently high to give definite evidence for the occurrence of the 5-HT(1D) receptor in the human brain.
Basal ganglia serotonin 1B receptors in parkinsonian monkeys with L-DOPA-induced dyskinesia
Biochem Pharmacol 2013 Oct 1;86(7):970-8.PMID:23954709DOI:10.1016/j.bcp.2013.08.005.
L-DOPA-induced dyskinesias (LID)s are abnormal involuntary movements limiting the chronic use of L-DOPA, the main pharmacological treatment of Parkinson's disease (PD). Serotonin receptors are thought to contribute to LID but serotonin 1B (5-HT1B) receptors have never been investigated in any primate models of PD and LID. Therefore, we measured 5-HT1B receptors with [(3)H]GR 125743 autoradiography in controls, MPTP-lesioned monkeys, and L-DOPA-treated MPTP monkeys, with or without Ro 61-8048 treatment, a kynurenine hydroxylase inhibitor alleviating LID. In normal condition, 5-HT1B receptor specific binding was highest in the substantia nigra pars reticulata (SNr), high in the globus pallidus (GP), nucleus accumbens and substantia innominata and lower in the caudate nucleus and putamen. 5-HT1B receptors were increased in caudate nucleus, putamen and SNr of MPTP monkeys compared to controls. L-DOPA-treated MPTP monkeys had elevated 5-HT1B receptor specific binding in caudate nucleus, putamen, SNr and internal GP. In all these brain regions, increases were prevented by co-administration of Ro 61-8048. No effect of MPTP lesion or treatment was observed for 5-HT1B specific binding in the external GP, nucleus accumbens and substantia innominata. This study is the first description in primates of altered brain 5-HT1B receptors associated with prevention of LID.
The role of 5-HT(1B/1D) receptors in the modulation of 5-hydroxytryptamine levels in the frontal cortex of the conscious guinea pig
Eur J Pharmacol 1997 May 12;326(1):23-30.PMID:9178651DOI:10.1016/s0014-2999(97)00156-8.
The role of 5-HT(1B/1D) receptors in modulating extracellular 5-hydroxytryptamine (5-HT) levels in the guinea pig was investigated with the non-selective 5-HT(1B/1D) receptor inverse agonist, methiothepin, and the selective 5-HT(1B/1D) receptor partial agonists, GR 127935 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5-me thyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-4-carboxamide) and GR 125743 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-3-methyl-4-(4-pyri dinyl)benzamide). Extracellular 5-HT levels were measured using the technique of brain microdialysis, in the frontal cortex of the freely moving guinea-pig. Extracellular 5-HT was tetrodotoxin sensitive and calcium dependent, and increased when perfused with a high concentration of K+. In addition, extracellular 5-HT levels were lowered by the 5-HT(1B/1D) receptor agonist, sumatriptan, and the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, while perfusion of the selective serotonin re-uptake inhibitor, paroxetine, increased 5-HT in a concentration-dependent manner. Perfusion of methiothepin, GR 127935 and GR 125743 into the frontal cortex caused significant but transient increases of extracellular 5-HT. However, systemic administration of methiothepin, GR 127935 and GR 125743, at 0.3 mg/kg i.p., produced significant decreases in extracellular 5-HT, to minima of 27 +/- 3%, 31 +/- 12% and 27 +/- 13% of basal, respectively. The increase of extracellular 5-HT, following 5-HT(1B/1D) receptor inverse and partial agonist perfusion into the frontal cortex, was probably a consequence of attenuation of an endogenous 5-HT tone at terminal 5-HT autoreceptors. The unexpected decrease in 5-HT levels following systemic administration may be a result of additional attenuation of endogenous 5-HT tone at cell body autoreceptors in the raphe. Such an increase in local 5-HT levels could then stimulate 5-HT1A receptors to inhibit cell firing and hence decrease 5-HT levels in the terminal regions. This was confirmed when co-administration of the 5-HT1A receptor antagonist, WAY 100635, significantly attenuated the GR 127935 decrease in 5-HT.
Withdrawal from chronic cocaine up-regulates 5-HT1B receptors in the rat brain
Neurosci Lett 2003 Nov 20;351(3):169-72.PMID:14623133DOI:10.1016/j.neulet.2003.08.007.
In the present study we examined the effect of prolonged treatment with cocaine (a sensitization and discrimination paradigm) on the expression of serotonin (5-HT)(1B) receptors in rat brain structures using a quantitative autoradiographic analysis. To estimate the distribution of 5-HT(1B) receptors in several brain coronal sections, we used [N-methyl-(3)H]GR 125743, a 5-HT(1B/1D) receptor antagonist, in the presence of ketanserin (a drug used to block 5-HT(1D) receptors). The binding of [N-methyl-(3)H]GR 125743 in the areas containing dopamine cell bodies (the ventral tegmental area, the substantia nigra) and terminals (the nucleus accumbens shell and core, but not in the caudate-putamen) and in the subiculum of the hippocampus was increased after withdrawal from repeated cocaine in both the discrimination and the sensitization paradigms, either being effective as confirmed by behavioral experiments. Neither acute cocaine injection nor the psychostimulant challenge following its repeated administration affected the binding of [N-methyl-(3)H]GR 125743 in the above brain areas. Our results indicate that withdrawal from chronic cocaine induces up-regulation of 5-HT(1B) receptors in a number of rat brain structures.