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CARDIOVASCULAR PROPERTIES OF 5-HT 1 RECEPTOR AGONISTS

5-HT 1 受体激动剂的心血管特性

基本信息

批准号：
3354188
负责人：
JOHN P LONG
金额：
$ 20.82万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-04-01 至 1991-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3354188
关键词：
alkyl group apomorphine artery occlusion bradycardia cardiovascular pharmacology carotid artery cats dogs guinea pigs hormone receptor laboratory rat parasympathetic nervous system serotonin sympathetic nervous system

项目摘要

5-HT1-receptor agonists are potent, long acting agents that lower arterial pressure and induce bradycardia in cats, dogs, and rats. 8-OH-2-di-n propylaminotetralin (8-OH DPAT) will serve as the reference chemical and will be compared with newly-synthesized apomorphine derivatives in which the 10-OH group is substituted with CH3, CH2OH, H, etc., as well as altering substitution on nitrogen (aporphines). Preliminary studies ahve demonstrated that the 10-CH3, N-CH3 aporphine derivative parallels closely the behavorial and cardiovascular changes-induced by 8-OH DPAT, a selective 5-HT1A receptor agonist. The aporphine compound has no interaction with DA2-receptors and our hypothesis is that alkyl substitutions in the 10-position of apomorphine introduce potent 5-HT1-receptor agonist properties. The experimental procedures will evaluate possible central and peripheral sites for the hypotensive and bradycardic responses induced by these series of compounds, investigate reflex activations of the sympathetic and parasympathetic nervous systems, and determine receptor selectively and specificity using various radioligand binding and bioassay procedures. Direct goals of this research include: (1) determine the role of 5- HT1 -receptors for control of the cardiovascular system, (2) evaluate present hypothesis is that these agents are potent 5-HT- receptor agonists, and both of these series of agents are very potent in blocking cardiovascular responses to bilateral carotid occlusion, inducing bradycardia and hypotension, (3) identifying agonists for serotonin-receptor subtypes; this is certainly needed to help define physiological roles of this receptor, and (4) since we have no selective antagonists for 5-HT1 receptors, an active agent is clearly needed and this research will identify antagonists for 5-HT1 receptor subtypes. This research will combine chemical and biological experimental procedures to advance our understanding of the role of 5-HT1 receptors in cardiovascular pharmacology.

5-HT 1受体激动剂是降低5-HT 1受体活性的强效长效剂。在猫、狗和大鼠中， 8-OH-2-二正丙基氨基四氢化萘（8-OH DPAT）将作为参考化学品并将与新合成的进行比较 10-OH基被取代的阿扑吗啡衍生物与CH3、CH2OH、H等反应，以及改变氮（阿朴啡）。初步研究表明， 10-CH 3，N-CH 3阿朴啡衍生物与 8-OH DPAT，a 选择性5-HT1A受体激动剂。阿朴啡化合物具有没有与DA 2受体的相互作用，我们的假设是，在阿扑吗啡的10位上的取代引入了有效的 5-HT1-受体激动剂性质。实验程序将评估可能的中央和水肿和心动过缓反应的外周部位诱导的，研究反射交感神经和副交感神经的激活系统，并确定受体选择性和特异性，各种放射性配体结合和生物测定程序。本研究的直接目标包括：（1）确定5- 控制心血管系统的HT1受体，（2）评估目前的假设是，这些药物是有效的5-HT- 受体激动剂，这两个系列的药物都非常有效阻断对双侧颈动脉闭塞，诱导心动过缓和低血压，（3）识别肾上腺素受体亚型激动剂;这是肯定需要的以帮助定义该受体的生理作用，以及（4）由于我们没有5-HT 1受体的选择性拮抗剂，很明显需要一种药物，这项研究将确定拮抗剂 5-HT1受体亚型。本研究将联合收割机化学和生物实验相结合促进我们对5-HT1作用的理解的程序心血管药理学受体。