AHR-16303B，5-HT2受体和电压敏感钙通道的新型拮抗剂。,Journal of Cardiovascular Pharmacology

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AHR-16303B，5-HT2受体和电压敏感钙通道的新型拮抗剂。
Journal of Cardiovascular Pharmacology ( IF 2.6 ) Pub Date : 1991-01-01 , DOI: 10.1097/00005344-199101000-00007
R J Barrett ₁ , K C Appell , B F Kilpatrick , A G Proakis , J C Nolan , D A Walsh

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使用体内和体外方法表征了AHR-16303B，这是一种对5-HT2受体和电压敏感钙通道具有拮抗作用的新型化合物。通过抑制（a）[3H]酮色林与大鼠大脑皮膜的结合（IC50 = 165 nM）证明了AHR-16303B的5-HT2受体拮抗特性。（b）5-羟色胺（5-HT）诱导的大鼠足水肿（最低有效剂量（MED）= 0.32 mg / kg口服，口服）；（c）自发性高血压大鼠（SHR）5-HT诱导的血管升压反应（ID50 =静脉内0.18 mg / kg（iv），口服1.8 mg / kg），（d）5-HT诱导的大鼠利尿作用（MED = 1 mg / kg po），和（e）5-HT + ADP（IC50 = 1.5 mM）诱导的血小板聚集。通过抑制（a）[3H]尼莫地平与兔骨骼肌膜上的电压敏感钙通道的结合（IC50 = 15 nM），证明了AHR-16303B的钙拮抗剂特性，（b）KCl刺激的钙通入培养的PC12中（IC50 = 81 nM），以及（c）CaCl2诱导的兔胸主动脉条收缩（pA2 = 8.84）。AHR-16303B对放射性配体与多巴胺2（DA2）α1，α2，H1、5-HT1α，β2，毒蕈碱M1或σ阿片受体的结合几乎没有影响。对5-HT3受体介导的迷走性心动过缓没有影响；并且对孤立的豚鼠心房仅产生较小的负性变力，变时性和变径作用。在有意识的SHR中，口服AHR-16303B 30 mg / kg可以在给药后3小时完全阻止血管加压药对iv 5-HT的反应，并使血压（BP）降低24％。

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AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels.

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H]ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [3H]nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.

更新日期：2019-11-01

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