L-765314
目录号 : GC32670L-765314 is a selective and potent α1b-adrenoceptor (α1b adrenergic receptor) antagonist with an IC50 of 1.90 nM and Kis of 5.4 and 2.0 for rat and human α1b adrenergic receptor, respectively.
Cas No.:189349-50-6
Sample solution is provided at 25 µL, 10mM.
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Animal experiment: | Rats[1]The potency of terazosin and L-765314 for inhibiting the pressor responses to phenylephrine and A-61603 is evaluated in anesthetized male Sprague-Dawley rats (n=4). The rats are dosed i.v with either vehicle or ascending doses of test compounds, and the peak changes in mean arterial pressure are measured. The dose of antagonist eliciting a 25 mmHg decrease in mean arterial pressure (AD25) is calculated as an index of hypotensive potency. The rats are dosed i.v with L-765314 at 3 mg/kg , and the plasma is assayed by LCMS for parent compound[1]. |
References: [1]. Patane MA, et al. 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6, 7-dimethoxyquinazoline (L-765,314): a potent and selective alpha1b adrenergic receptor antagonist. J Med Chem. 1998 Apr 9;41(8):1205-8. |
L-765314 is a selective and potent α1b-adrenoceptor (α1b adrenergic receptor) antagonist with an IC50 of 1.90 nM and Kis of 5.4 and 2.0 for rat and human α1b adrenergic receptor, respectively.
L-765,314 is a potent and selective α1b adrenergic receptor antagonist, which also reduces melanin production by targeting the protein kinase C (PKC)-dependent regulation of tyrosinase activity and raises the intracellular level of melanin precursors.[2]
[1] Patane MA, et al. Journal of Medicinal Chemistry, 41(8), 1205–1208. [2] Kim J, et al. Molecules. 2019 Feb 21;24(4):773.
Cas No. | 189349-50-6 | SDF | |
Canonical SMILES | O=C(N1[C@H](C(NC(C)(C)C)=O)CN(C2=NC(N)=C3C=C(OC)C(OC)=CC3=N2)CC1)OCC4=CC=CC=C4 | ||
分子式 | C27H34N6O5 | 分子量 | 522.6 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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10 mM | 0.1914 mL | 0.9568 mL | 1.9135 mL |
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Noradrenaline contracts rat retinal arterioles via stimulation of α(1A)- and α(1D)-adrenoceptors
Eur J Pharmacol 2011 Dec 30;673(1-3):65-9.PMID:22040923DOI:10.1016/j.ejphar.2011.10.012.
The aim of this study was to characterize the α₁-adrenoceptor subtype(s) involved in the noradrenaline-induced contraction of retinal arterioles in rats. In vivo ocular fundus images were captured with a digital camera equipped with a special objective lens. By measuring changes in diameter of retinal arterioles in the fundus images, retinal vascular response was assessed. The systemic blood pressure and heart rate in the animals were also continuously recorded. Following blockade of β₁/β₂-adrenoceptors with propranolol, noradrenaline (0.03-3 μg/kg/min, i.v.) decreased the diameter of retinal arterioles and increased the mean blood pressure in a dose-dependent manner. The highest dose (3 μg/kg/min, i.v.) of noradrenaline caused a small increase in heart rate. The α(1A)-adrenoceptor antagonist RS100329 (0.1 mg/kg, i.v.) and the α(1D)-adrenoceptor antagonist BMY 7378 (1 mg/kg, i.v.) significantly prevented noradrenaline-induced contraction of retinal arterioles and pressor responses whereas the α(1B)-adrenoceptor antagonist L-765314 (1 mg/kg, i.v.) did not. The α(1A)-adrenoceptor agonist, A 61603 (0.03-0.3 μg/kg/min, i.v.), also caused contractile responses of retinal arterioles and pressor responses. These responses were almost completely prevented by RS100329 (0.1 mg/kg, i.v.), but not by BMY 7378 (1 mg/kg, i.v.). These results suggest that the contractile effects of noradrenaline on retinal arterioles and peripheral resistance vessels are, at least in part, mediated by stimulation of α(1A)- and α(1D)-adrenoceptors. Furthermore, it is likely that the α₁-adrenoceptor subtype(s) involved in rat vascular responses are similar in both retinal and peripheral circulation.
Functional characterization of alpha-adrenoceptors mediating pupillary dilation in rats
Eur J Pharmacol 2003 Jun 20;471(2):135-40.PMID:12818701DOI:10.1016/s0014-2999(03)01824-7.
Previously, we reported that the alpha(1A)-adrenoceptor, but not the alpha(1D)-adrenoceptor, mediates pupillary dilation elicited by sympathetic nerve stimulation in rats. This study was undertaken to further characterize the alpha-adrenoceptor subtypes mediating pupillary dilation in response to both neural and agonist activation. Pupillary dilator response curves were generated by intravenous injection of norepinephrine in pentobarbital-anesthetized rats. Involvement of alpha(1)-adrenoceptors was established as mydriatic responses were inhibited by systemic administration of nonselective alpha-adrenoceptor antagonists, phentolamine (0.3-3 mg/kg) and phenoxybenzamine (0.03-0.3 mg/kg), as well as by the selective alpha(1)-adrenoceptor antagonist, prazosin (0.3 mg/kg). The alpha(2)-adrenoceptor antagonist, rauwolscine (0.5 mg/kg), was without antagonistic effects. alpha(1A)-Adrenoceptor selective antagonists, 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101; 0.1-1 mg/kg) and 5-methylurapidil (0.1-1 mg/kg), the alpha(1B)-adrenoceptor selective antagonist, 4-amino-2-[4-[1-(benzyloxycarbonyl)-2(S)- [[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline (L-765314; 0.3-1 mg/kg), as well as the alpha(1D)-adrenoceptor selective antagonist, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY-7378; 1 mg/kg), were used to delineate the adrenoceptor subtypes involved. Mydriatic responses to norepinephrine were significantly antagonized by intravenous administration of both WB-4101 and 5-methylurapidil, but neither by L-765314 nor by BMY-7378. L-765314 (0.3-3 mg/kg, i.v.) was also ineffective in inhibiting the mydriasis evoked by cervical sympathetic nerve stimulation. These results suggest that alpha(1B)-adrenoceptors do not mediate sympathetic mydriasis in rats, and that the alpha(1A)-adrenoceptor is the exclusive subtype mediating mydriatic responses in this species.
Phenylephrine-Induced Contraction in Guinea Pig Thoracic Aorta Is Triggered by Stimulation of α1L-Adrenoceptors Functionally Coupled with Store-Operated Ca2+ Channels and Voltage-Dependent Ca2+ Channels
Biol Pharm Bull 2023;46(2):309-319.PMID:36724959DOI:10.1248/bpb.b22-00754.
We examined whether the α1L-adrenoceptor (AR), which shows low affinity (pA2 < 9) for prazosin (an α1-AR antagonist) and high affinity (pA2 ≈ 10) for tamsulosin/silodosin (α1A-AR antagonists), is involved in phenylephrine-induced contractions in the guinea pig (GP) thoracic aorta (TA). Intracellular signaling induced by α1L-AR activation was also examined by focusing on Ca2+ influx pathways. Tension changes of endothelium-denuded TAs were isometrically recorded and mRNA encoding α-ARs/Ca2+ channels and their related molecules were measured using RT-quantitative PCR. Phenylephrine-induced contractions were competitively inhibited by prazosin/tamsulosin, and their pA2 value were calculated to be 8.53/9.74, respectively. These contractions were also inhibited by silodosin concentration-dependently. However, the inhibition was not competitive fashion with the apparent pA2 value being 9.48. In contrast, phenylephrine-induced contractions were not substantially suppressed by L-765314 (an α1B-AR antagonist), BMY 7378 (an α1D-AR antagonist), yohimbine, and idazoxan (α2-AR antagonists). Phenylephrine-induced contractions were markedly inhibited by YM-254890 (a Gq protein inhibitor) or removal of extracellular Ca2+, and partially inhibited by verapamil (a voltage-dependent Ca2+ channel (VDCC) inhibitor). The residual contractions in the presence of verapamil were slightly inhibited by LOE 908 (a receptor-operated Ca2+ channel (ROCC) inhibitor) and strongly inhibited by SKF-96365 (a store-operated Ca2+ channel (SOCC) and ROCC inhibitor). Among the mRNA encoding α-ARs/SOCC-related molecules, α1A-AR (Adra1a)/Orai3, Orai1, and Stim2 were abundant in this tissue. In conclusion, phenylephrine-induced contractions in the GP TA can be triggered by stimulation of Gq protein-coupled α1L-AR, followed by activation of SOCCs and VDCCs.