Does Anesthetic Solubility Determine Receptor Specificity?

麻醉溶解度决定受体特异性吗？

• 批准号: 7991760
• 负责人: Robert Joseph Brosnan
• 金额: $ 22.96万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991760
• 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

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）：在本项目中，我们建议研究药物的水溶性与该药物对可能介导全身麻醉期间不动和/或遗忘的受体的特异性之间的关系。我们已经收集了大量的初步数据，表明药物调制的至少两个麻醉剂敏感的受体是预测的摩尔水溶性的“截止”值。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，我们将表达麻醉剂敏感性受体（例如，GABAA、NMDA等）在青蛙卵母细胞和测量抑制或增强电流产生的同源烃链。同系物烃含有相同的官能团，但在烃链的α-末端处相差1-2个碳（例如，1-丙醇对1-己醇）。利用各种各样的碳氢化合物具有巨大的不同的蒸汽压和分子大小和电荷，碳氢化合物的水溶性作为一个单一的关键的物理决定因素的麻醉剂敏感的受体在体外截止效应的效果可以证明。该临界摩尔水溶解度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，临界摩尔水溶解度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受体两者。 在特定目标2中，我们旨在测试在之前的体外研究中描述的麻醉剂溶解度特异性“截止值”是否转化为在全动物模型中对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）下异氟烷对NMDA贡献的研究中试点的药理学方法，研究2种同源吸入麻醉烃（烷烃）和2种同源注射麻醉烃（丙泊酚及其卤代类似物）的相对NMDA拮抗作用。由于每对同源麻醉剂的水溶性值均在特异性“截止”值的两侧，我们假设MAC处的NMDA拮抗作用仅存在于对中可溶性更高的化合物中，而可溶性更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。 公共卫生相关性：麻醉剂调节多种细胞受体，这些受体反过来又可以介导期望的和不期望的效果。细胞受体的这种新的溶解度-特异性“截止”现象的验证提供了一种简单地通过改变现有试剂的水溶性来开发更安全的麻醉剂的机制。降低某些药物的水溶性可以增加受体特异性，从而可能减少不良药物副作用。增加其他药物的水溶性可能增加所需的受体调节，具有使非麻醉剂具有全身麻醉剂的固定作用的潜力。水溶性作为药物-受体调节的决定因素的作用也将为细胞受体蛋白周围的水界面位点的麻醉作用理论提供额外的支持。