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受体的特异性之间的关系，这些受体可能会介导一般麻醉期间可能介导固定性和/或失忆症。我们已经收集了广泛的初步数据，这些数据表明，摩尔水溶性“截止”值预测了至少两个麻醉敏感受体的药物调节。我们建议使用青蛙卵母细胞中的体外电生理研究（特定目标1）确认这种溶性 - 特异性关系，然后使用大鼠的药理学研究测试这些相同的关系在体内是否存在（特定目标2）。在特定的目标1中，我们将在青蛙卵母细胞中表达麻醉敏感的受体（例如，GABAA，NMDA等），并测量对同源烃链产生的电流的抑制或增强。同源碳氢化合物包含相同的功能组，但在碳氢化合物链的＆端（例如1-丙醇与1-己醇）的＆ - 末端不同。利用具有巨大不同蒸气压，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解度作为体外切断效应对麻醉敏感受体的单个关键物理决定因素的影响。这种关键的摩尔水溶性截止值将定义化合物的体外特异性，用于两个受体之一。例如，在NMDA和GABAA受体调节的情况下，关键的摩尔水溶性将预测药物是否仅调节GABAA受体，或者药物是否能够调节NMDA和GABAA受体。在特定目标2中，我们旨在测试先前的体外研究中描述的麻醉溶解度特异性“截止性”是否转化为GABAA的特异性，而GABAA与NMDA受体调制中的特异性是否在整个动物模型中。 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.由于每对特异性“截止”值的两侧的每一对麻醉剂都将具有水溶性值，因此我们假设只有Mac的NMDA拮抗作用仅适用于这对较易溶的化合物，而较不溶的化合物则不应在任何递送的浓度下表现出NMDA受体拮抗作用的证据。公共卫生相关性：麻醉剂调节多个细胞受体，这些受体反过来又可以介导期望的和不良的作用。对细胞受体的这种新型溶解度的验证 - 特异性“截止性”现象提供了一种机制，可以简单地通过改变现有剂的水溶解度来开发更安全的麻醉剂。某些药物的水溶解度降低可能会增加受体特异性，从而有可能降低不良药物的副作用。其他药物的水溶性提高可能会增加理想的受体调节，从而可能将非麻醉剂与全身麻醉的固定作用浸泡。水溶解度作为药物受体调节的决定因素也将为细胞受体蛋白周围水性界面部位的麻醉作用理论增加支持。