Does Anesthetic Solubility Determine Receptor Specificity?

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全身麻醉期间可能介导不动和/或健忘症的受体的特异性之间的关系。我们收集了大量的初步数据，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。我们建议在青蛙卵母细胞的体外电生理研究中证实这种溶解度-特异性关系（Specific Aim 1），然后在大鼠的体内药理学研究中测试这些关系是否存在（Specific Aim 2）。在Specific Aim 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。同源烃含有相同的官能团，但在烃链的&端相差1-2个碳（例如，1-丙醇与1-己醇）。利用具有巨大不同蒸汽压、分子大小和电荷的各种碳氢化合物，可以证明碳氢化合物水溶性作为对麻醉敏感受体体外切断效应的单一关键物理决定因素的影响。这个临界摩尔水溶性临界值将确定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Specific Aim 2中，我们的目标是在全动物模型中测试先前体外研究中描述的麻醉剂溶解度特异性“截止点”是否转化为GABAA对NMDA受体调节的特异性。为此，我们将研究2种同源吸入麻醉烃（烷烃）和2种同源注射麻醉烃（异丙酚及其卤化类似物）的相对NMDA拮抗作用，使用我们在研究中试验的药理学方法，测量大鼠最低肺泡浓度（MAC）下异氟醚对NMDA的贡献。由于每一对同源的麻醉剂在特异性“截止”值的两侧都有一个水溶性值，我们假设在MAC处，NMDA拮抗作用只存在于可溶性较强的化合物中，而可溶性较弱的化合物在任何递送浓度下都不会表现出NMDA受体拮抗作用。

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.