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Biological Activity
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Description
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BRL-15572 is a 5-HT1D antagonist with pKi of 7.9. |
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Targets
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5-HT1D |
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IC50 |
7.9 (pKi) [1] |
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In Vitro
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BRL-15572 displays high affinity and selectivity for h5-HT1D receptors. BRL-15572 has 60-fold higher affinity for h5-HT1D than 5-HT1B receptors. BRL-15572 binds to h5-HT1B and h5-HT1D receptors with pKB of less than 6 and 7.1, respectively. BRL-15572 stimulates [35S]GTP γ S binding in both cell lines, with potencies that correlated with their receptor binding affinities in both h5-HT1B and h5-HT1D receptor expressing cell lines. BRL-15572 reveals receptor binding affinities for 5-HT1A, 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 with pKi of 7.7, 6.1, 5.2, 6.0, 6.6, 7.4, 6.2, 5.9 and 6.3, respectively. In the h5-HT1D cell line, both BRL-15572 (1 μM) shifts the 5-HT concentration response curve with pKB of 7.1, respectively. BRL-15572 does have moderately high affinity at human 5-HT1A and 5-HT2B receptors. [1] In human atrial appendages, the electrically evoked tritium overflow was inhibited by 5-HT in a manner susceptible to antagonism by BRL-15572 (300 nM; 23 times Ki at h5-HT1D receptors). [2] The inhibitory effect of 5-HT on the K+-evoked overflow of glutamate is antagonized by the h5-HT1D receptor ligand BRL-15572. BRL-15572 (1 μM) is unable to modify the effect of 5-HT at the autoreceptor regulating [3H]5-HT release. [3] The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibits the effect of the agonist L-694 247. [4] |
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In Vivo
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In diabetic pithed rats, administration of the selective 5-HT1D receptor antagonist BRL-15572 (2 mg/kg) does not modify the decreased HR induced by vagal electrical stimulation. The effects of L-694,247 (50 μg/kg), a selective agonist for non-rodent 5-HT1B and 5-HT1D receptors, on the vagally induced bradycardia are not apparent after pretreatment with BRL-15572. [5] |
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Clinical Trials
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Features
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BRL 15572 is a selective 5-HT1D/1B receptor antagonist. |
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Protocol
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Cell Assay
[1]
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| Cell Lines |
CHO cells expressing the h5-HT1B or h5-HT1D receptors |
| Concentrations |
0 μM -10 μM |
| Incubation Time |
30 minutes |
| Methods |
[35S]GTPγS binding studies. [35S]GTPγS binding studies in CHO cells expressing the h5-HT1B or h5-HT1D receptors are performed. In brief, membranes from 1 × 106 cells are preincubated at 30°C for 30 minutes, in HEPES buffer (HEPES [20 mM], MgCl 2 [3 mM], NaCl [100 mM], ascorbate [0.2 mM]), containing GDP (10 μ M), with or without BRL-15572. The reaction is started by the addition of 10 μL of [35S]GTPγS (100 pM, assay concentration) followed by a further 30 minutes incubation at 30°C. Non-specific binding is determined by addition of unlabelled GTPγS (10 μM), prior to the addition of cells. The reaction is stopped by rapid filtration using Whatman GF/B grade filters followed by five washes with ice-cold HEPES buffer. Radioactivity is determined by liquid scintillation spectrometry. |
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Animal Study
[5]
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| Animal Models |
Male Wistar rats with diabetes |
| Formulation |
20% propylene glycol |
| Doses |
1 mg/kg, 2 mg/kg |
| Administration |
Administered via i.v. |
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References |
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[1] Price GW, et al. Naunyn Schmiedebergs Arch Pharmacol. 1997, 356(3), 312-320.
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[2] Schlicker E, et al. Naunyn Schmiedebergs Arch Pharmacol. 1997, 356(3), 321-327.
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[3] Marcoli M, et al. Br J Pharmacol. 1999, 126(3), 607-612.
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[4] Calama E, et al. Clin Exp Pharmacol Physiol. 2005, 32(10), 894-900.
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[5] García M, et al. Clin Exp Pharmacol Physiol. 2007, 34(11), 1199-1206.
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[6] Valdivia LF, et al. Naunyn Schmiedebergs Arch Pharmacol. 2004, 370(1), 46-53.
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