RS 39604:一个强有力的、选择性和口头活跃5-HT4受体拮抗剂。

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对冲基金党卫军,Bonhaus DW,约翰逊LG、梁E,克拉克RD, Eglen RM

RS 39604:一个强有力的、选择性和口头活跃5-HT4受体拮抗剂。

Br J杂志。1995年7月,115 (6):1087 - 95。doi: 10.1111 / j.1476-5381.1995.tb15922.x。

PubMed ID
7582507 (在PubMed
]
文摘

1。选择性5-HT4受体拮抗作用可能在心肌的某些疾病提供治疗中获益,滋养和降低尿路。我们现在报告RS 39604、小说和选择性5-HT4受体拮抗剂和比较其药理特性与某人204070。2。在天竺鼠纹状体膜,RS 39604年和204070年某人抑制特定绑定的[3 h] gr 113808浓度的方式产生pKi的估计9.1和10.9,分别。RS 39604显示低亲和力(pKi < 6.5)为5-HT1A, 5-HT2C 5-HT3,α1 c, D1, D2, M1, M2, AT1、B1和μ阿片受体和温和的亲和力为σ1,σ(pKi = 6.8)和2 (pKi = 7.8)的网站。3所示。大鼠孤立的食道,卡巴可预约,RS 39604 (30 - 300 nM)作为竞争对手对待5-HT-induced放松(pA2 = 9.3;席尔德斜率= 1.0)。我们和其他人显示之前,某人204070表现为不能超越的对手在这个准备(pA2大约10.5)。 In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4. In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 micrograms kg-1, i.v. and 254.5 micrograms kg-1, i.duod). At maximal doses of 30 micrograms kg-1, i.v. and 6 mg kg-1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h. In this preparation, SB 204070 was as potent as RS 39604by the i.v. route but was inactive by the intraduodenal route at doses up to 3 mg kg-1.5. In conscious mice, RS 39604, administered by the i.p. or p.o. route, produced dose-depend entinhibition of 5-hydroxytryptophan (5-HTP)-induced diarrhoea (ID50= 81.3 microg kg-1, i.p. and 1.1 mg kg-1,p.o.). In this assay, SB 204070 was inactive by the oral route at doses up to 30 mg kg-1.6. In anaesthetized guinea-pigs, RS 39604 antagonized the contractile effect of 5-HT in the proximal colon by producing parallel, dextral displacement of the dose-response curve to 5-HT. The mean dose ratios to 5-HT at 0.1 mg kg-1, i.v., 1 mg kg-1, i.v. and 10 mg kg-1, i.duod. were 4.6, 30.7 and 10.8,respectively. SB 204070 behaved as an unsurmountable antagonist in this assay.7. In a model of visceral pain in conscious rats, RS 39604 (0.01-1 mg kg-1, i.v.) did not affect colorectal distension-induced increases in arterial pressure whereas morphine (1 mg kg-1, i.v.) produced significant inhibition of the response, implying that 5-HT4 receptors are not involved in nociception in this model.8. The data suggest that RS 39604 is a high affinity and selective 5-HT4 receptor antagonist that is orally active and long-lasting in vivo. It is concluded that RS 39604 may be the preferable probe to use for investigating the physiological and pathophysiological role of 5-HT4 receptors in vivo.

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