Does Anesthetic Solubility Determine Receptor Specificity?

描述(申请人提供)：在这个项目中，我们建议研究药物的水溶性和该药物对受体的特异性之间的关系，该受体可能介导全身麻醉期间的不动和/或健忘。我们已经收集了大量的初步数据，表明至少两个麻醉剂敏感受体的药物调节是通过摩尔溶解度“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研究(特定目标1)来确认这种溶解度-特异性关系，然后使用大鼠体内的药理学研究(特定目标2)来检验这些相同的关系是否存在。在特定的目标1中，我们将表达麻醉敏感受体(如GABAA、NMDA等)。并测量同源碳氢链产生的电流的抑制或增强。同系烃含有相同的官能团，但在碳氢链的&端有1-2个不同的碳(例如，1-丙醇与1-己醇)。利用蒸汽压、分子大小和电荷差异很大的不同碳氢化合物，可以证明碳氢化合物的水溶性作为体外切断麻醉剂敏感受体效应的单一关键物理决定因素的影响。这一临界摩尔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，临界摩尔溶解度将预测一种药物是否只调节GABAA受体，或者一种药物是否能够调节NMDA和GABAA受体。在特定的目标2中，我们的目标是在全动物模型中测试先前体外研究中所描述的麻醉剂的溶解性-特异性“截止”是否翻译为GABAA与NMDA受体调节的特异性。为此，我们将用药理学方法研究两种同源吸入麻醉剂(烷烃)和两种同源注射麻醉剂(异丙酚及其卤代类似物)对NMDA的相对拮抗作用，这是我们在测定大鼠肺泡最低浓度(MAC)时异氟醚对NMDA贡献的研究中尝试的。由于每一对同源麻醉药在特异性“截止”值的两侧都有一个水溶度值，我们假设在MAC处的NMDA拮抗作用只存在于这对麻醉药中较易溶的那对，而较难溶的化合物在任何给药浓度下都不应该表现出NMDA受体拮抗的证据。 公共卫生相关性：麻醉药调节多个细胞受体，这些受体反过来可以调节理想和不理想的效果。对细胞受体这种新的溶解性特异性“切断”现象的验证，为开发更安全的麻醉药提供了一种机制，只需改变现有药物的水溶性即可。降低某些药物的水溶性可以增加受体的特异性，从而潜在地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理想的受体调节，有可能使非麻醉剂具有全身麻醉剂的固定效果。作为药物受体调节的决定因素，水溶性的作用也将增加对细胞受体蛋白周围水界面处的麻醉作用理论的额外支持。

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.