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Does Anesthetic Solubility Determine Receptor Specificity?

麻醉溶解度决定受体特异性吗？

基本信息

批准号：
8527802
负责人：
Robert Joseph Brosnan
金额：
$ 29.42万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527802
关键词：
1-Propanol Adverse drug effect Affect Affinity Alkanes Alveolar Amnesia Anesthetics Animal Model Breathing Bromides Carbon Cell membrane Cells Charge Chemosensitization Data Development Dose Drug Modulation Drug Receptors Electrodes Exhibits General Anesthesia General anesthetic drugs Glycine Receptors Hexanols Hydrocarbons In Vitro Injectable Ion Channel Isoflurane Location Measures Mediating Membrane Methods N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Oocytes Pharmaceutical Preparations Potassium Channel Propofol Proteins Rana Rattus Receptor Cell Relative (related person)Role SCN2A protein Shapes Side Site Sodium Channel Solubility Specificity Testing Translating Validation Water analog aqueous base functional group in vivo interfacial molecular size novel potassium channel protein TREK-1 pressure public health relevance receptor response theories vapor voltage voltage clamp water solubility

项目摘要

DESCRIPTION (provided by applicant): In this project, we propose to study the relationship between the water solubility of a drug and the specificity of that drug for receptors that may mediate immobility and/or amnesia during general anesthesia. We have collected extensive preliminary data that suggest drug modulation of at least two anesthetic-sensitive receptors is predicted by a molar water solubility "cut-off" value. We propose to confirm this solubility- specificity relationship using in vitro electrophysiological studies in frog oocytes (Specific Aim 1) and then to test whether these same relationships exist in vivo using pharmacologic studies in rats (Specific Aim 2). In Specific Aim 1, we will express anesthetic-sensitive receptors (e.g., GABAA, NMDA, etc.) in frog oocytes and measure the inhibition or potentiation of currents produced by homologous hydrocarbon chains. Homologous hydrocarbons contain the same functional group, but differ by 1-2 carbons at the &-end of the hydrocarbon chain (e.g., 1-propanol vs. 1-hexanol). Utilizing a diverse range of hydrocarbons having vastly different vapor pressures and molecular sizes and charges, the effect of hydrocarbon water solubility as a single critical physical determinant of an in vitro cut-off effect on anesthetic-sensitive receptors can be demonstrated. This critical molar water solubility cut-off value will define in vitro specificity of a compound for one of two receptors. For example, in the case of NMDA and GABAA receptor modulation, the critical molar water solubility will predict whether a drug modulates GABAA receptors only or whether a drug is able to modulate both NMDA and GABAA receptors. In Specific Aim 2, we aim to test whether the anesthetic solubility-specificity "cut-off" described in the previous in vitro studies translate into specificity for GABAA versus NMDA receptor modulation in a whole-animal model. To this end, we will study the relative NMDA antagonism of 2 homologous inhaled anesthetic hydrocarbons (alkanes) and 2 homologous injectable anesthetic hydrocarbons (propofol and its halogenated analogue) using pharmacologic methods we have piloted in studies measuring the contribution of NMDA by isoflurane at minimum alveolar concentration (MAC) in rats. Since each homologous pair of anesthetics will have a water solubility value on either side of the specificity "cut-off" value, we hypothesize that NMDA antagonism at MAC will exist only for the more soluble of the pair, whereas the less soluble compound should never exhibit evidence of NMDA receptor antagonism at any delivered concentration. PUBLIC HEALTH RELEVANCE: Anesthetics modulate multiple cell receptors, and these receptors can in turn mediate both desirable and undesirable effects. Validation of this novel solubility- specificity "cut-off" phenomenon for cell receptors provides a mechanism for the development of safer anesthetics simply by altering the water solubility of existing agents. Decreasing water solubility of some drugs could increase receptor specificity and thus could potentially reduce undesirable drug side-effects. Increasing water solubility of other drugs might add desirable receptor modulation, with the potential to imbue a non- anesthetic with the immobilizing effects of a general anesthetic. The role of water solubility as a determinant of drug-receptor modulation would also add additional support to theories of anesthetic action at aqueous interfacial sites around cell receptor proteins.

描述（由申请人提供）：在该项目中，我们建议研究药物的水溶性与该药物对全身麻醉期间可能介导不动和/或遗忘的受体的特异性之间的关系。我们收集了广泛的初步数据，表明至少两种麻醉敏感受体的药物调节是通过摩尔水溶性“截止”值来预测的。我们建议使用青蛙卵母细胞的体外电生理学研究来确认这种溶解度-特异性关系（具体目标 1），然后使用大鼠的药理学研究来测试这些相同的关系是否存在于体内（具体目标 2）。在具体目标 1 中，我们将在青蛙卵母细胞中表达麻醉敏感受体（例如 GABAA、NMDA 等），并测量同源烃链产生的电流的抑制或增强。同系烃含有相同的官能团，但烃链末端有 1-2 个碳不同（例如，1-丙醇与 1-己醇）。利用具有截然不同的蒸气压、分子大小和电荷的多种碳氢化合物，可以证明碳氢化合物水溶性作为对麻醉敏感受体的体外截止效应的单一关键物理决定因素的影响。该临界摩尔水溶性截止值将定义化合物对两种受体之一的体外特异性。例如，在 NMDA 和 GABAA 受体调节的情况下，临界摩尔水溶性将预测药物是否仅调节 GABAA 受体或药物是否能够调节 NMDA 和 GABAA 受体。在具体目标 2 中，我们旨在测试先前体外研究中描述的麻醉溶解度特异性“截止”是否转化为整体动物模型中 GABAA 与 NMDA 受体调节的特异性。为此，我们将使用我们在测量大鼠最低肺泡浓度（MAC）下异氟醚对 NMDA 的贡献的研究中试点的药理学方法，研究 2 种同源吸入麻醉碳氢化合物（烷烃）和 2 种同源注射麻醉碳氢化合物（异丙酚及其卤化类似物）的相对 NMDA 拮抗作用。由于每对同源麻醉剂在特异性“截止”值的两侧都有一个水溶性值，因此我们假设 MAC 处的 NMDA 拮抗作用仅存在于该对中溶解度较高的化合物中，而溶解度较低的化合物在任何递送浓度下都不应表现出 NMDA 受体拮抗作用的证据。公共健康相关性：麻醉剂调节多种细胞受体，而这些受体反过来又可以介导所需的和不良的效应。对细胞受体的这种新型溶解度特异性“截止”现象的验证提供了一种通过改变现有药剂的水溶性来开发更安全麻醉剂的机制。降低某些药物的水溶性可以增加受体特异性，从而有可能减少不良的药物副作用。增加其他药物的水溶性可能会增加所需的受体调节，有可能使非麻醉剂具有全身麻醉剂的固定作用。水溶性作为药物受体调节决定因素的作用也将为细胞受体蛋白周围水界面位点的麻醉作用理论提供额外的支持。