Use of stereoisomers of zacopride to analyze actions of 5-hydroxytryptamine on enteric neurons.
Use of stereoisomers of zacopride to analyze actions of 5-hydroxytryptamine on enteric neurons.
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使用扎考必利的立体异构体分析 5-羟色胺对肠神经元的作用。
DOI：
10.1152/ajpgi.1991.260.1.g80
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Gershon,MD
中科院分区：
文献类型：
--
作者：
Wade,PR;Mawe,GM;Branchek,TA;Gershon,MD
在豚鼠肌间神经丛的2-AH型神经元上发现了兴奋性5-羟色胺(5-HT)受体的两种亚型：5-HT1P和5-HT3。5-HT1P受体介导这些细胞的慢去极化，5-HT3受体介导快速去极化，然而，这些受体在肠道生理中的作用尚不清楚。雷扎必利(BRL 24924)是一种取代苯甲酰胺，先前已被发现拮抗5-HT1P和5-HT3受体介导的肌间神经元的反应。为了进一步了解5-羟色胺受体的功能，我们研究了结构相似的苯甲酰胺扎克必利对肌间2-AH神经元的影响。与伦氮比利相反，S-，而不是R-扎可必利，被发现模拟5-HT1P受体介导的对5-羟色胺的慢反应。用5-羟色胺脱敏5-HT1P受体可抑制S-扎克必利的慢去极化反应，用S-扎克必利脱敏可拮抗5-羟色胺的慢反应。对S-扎克必利的反应也可被5-羟色胺受体拮抗剂5-羟色胺(5-N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan-DP)和伦扎必利抑制。S-扎可普利与瑞氮比利和5-羟色胺一样，对突触前快兴奋性突触后电位有抑制作用，该作用可通过5-羟色胺1P或5-羟色胺1a受体介导。扎可必利的S和R立体异构体均拮抗5-HT3受体介导的对5-羟色胺的快速反应。与5-HTP-DP不同，扎克必利及其立体异构体和雷氮比利都不能抑制5-[~3H]HT与5-HT1P受体的结合。[~3H]扎可必利(5-10 NM)被发现与肠道中的一个部位结合，超过1000倍的伦氮比利和超过5-羟色胺受体拮抗剂ICS205-930的S-扎可必利(但不是R-扎可必利)可以从该部位移位。这些观察表明，除了5-HT3受体外，肌间神经元上还有一个苯甲酰胺结合部位，它与5-HT1P受体的5-HT识别部位相互作用，但不同于5-HT1P受体的识别部位。苯甲酰胺可能影响5-HT1P受体与其效应器的偶联。
Two subtypes of excitatory 5-hydroxytryptamine (5-HT) receptor, 5-HT1P and 5-HT3, are found on type 2-AH neurons of the guinea pig myenteric plexus. The 5-HT1P receptor mediates a slow and the 5-HT3 receptor a fast depolarization of these cells, however, the role of these receptors in the physiology of the gut is unknown. Renzapride (BRL 24924), a substituted benzamide, has previously been found to antagonize responses of myenteric neurons mediated by both 5-HT1P and 5-HT3 receptors. The effects on myenteric type 2-AH neurons of a structurally similar benzamide, zacopride, which unlike renzapride has S and R stereoisomers, were investigated to gain further insight into 5-HT receptor function. In contrast to renzapride, S-, but not R-zacopride, was found to mimic the 5-HT1P receptor-mediated slow response to 5-HT. Desensitization of 5-HT1P receptors with 5-HT inhibited slow depolarizing responses to S-zacopride, and desensitization with S-zacopride antagonized slow responses to 5-HT. Responses to S-zacopride were also inhibited by renzapride and the 5-HT1P receptor antagonist N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP). S-zacopride, like renzapride and 5-HT, presynaptically inhibited nicotinic fast excitatory postsynaptic potentials, an effect that can be mediated by 5-HT1P or 5-HT1A receptors. Both S and R stereoisomers of zacopride antagonized 5-HT3 receptor-mediated fast responses to 5-HT. Unlike 5-HTP-DP, neither zacopride or its stereoisomers nor renzapride inhibited the binding of 5-[3H]HT to 5-HT1P receptors. [3H]zacopride (5-10 nM) was found to bind to a site in the gut from which it could be displaced by a 1,000-fold excess of renzapride and S-zacopride (but not R-zacopride) greater than 5-HTP-DP much greater than the 5-HT3 receptor antagonist ICS 205-930. These observations suggest that, in addition to 5-HT3 receptors, there is a benzamide binding site on myenteric neurons that interacts with, but is distinct from, the 5-HT recognition site of 5-HT1P receptors. Benzamides may affect coupling of the 5-HT1P receptor to its effector.