A Medicinal Chemistry Approach to Understanding the Basis of Olfactory Perception

描述（由申请人提供）：将气味剂的化学结构与其受体联系起来是感觉生理学中的一个长期问题。它强调了澄清配体-受体相互作用的必要性，特别是在如何最有意义地定义复杂的化学刺激方面。识别化学刺激物的相关特征的挑战是气味剂和药物所共有的。因此，了解哺乳动物外周嗅觉系统的气味受体（OR）如何在功能上对气味进行分类可能有助于合理的药物设计，特别是在OR所属的G蛋白偶联受体的A类亚型中。 目前，气味剂之间的功能关系尚不清楚。气味剂的相关尺寸不是直观的。虽然大多数其他初级感觉皮层都有反映刺激中气味的“地图”，但梨状皮层没有明确的化学位置图来指导化学空间中哪些气味是“邻近的”。在没有其他指导的情况下，气味的默认组织来自有机化学。但嗅觉悖论表明，这种传统的气味分类方法是不够的。一些感知物，如麝香，可以通过高度不同的化学结构引起。然而，高度相似的化学结构，如香芹酮的对映异构体，有时会引起明显的非重叠感知。一个问题可能是有机化学强调那些影响合成反应方案的特征。这些特征在生物环境中可能不具有相同的相关性。 需要一种与生物学更相关的气味分类。药物化学可以帮助提供这种新的视角，因为它强调化合物的生物功能而不是其化学形式。一些化学片段取代药物化学中心产生的化合物，似乎不一致，但这些化合物往往保持功能，在其预期的目标，一种现象称为生物电子等排。我们建议挑战的能力，不同的OR接受三个关键的药物化学片段取代：交换芳香环，反转酯，和生物电子等排取代脂肪族支架的苯环。如果通过这些片段取代相关的气味剂在整个OR库中引起相似的活性模式，则将支持使用OR作为药物筛选的天然多样性平台。我们还将确定由各种取代激活的特异性受体，以开发一种新的基于功能的气味受体家族分类。

DESCRIPTION (provided by applicant): Linking the chemical structure of an odorant to its percept is a longstanding problem in sensory physiology. It underscores the need to clarify ligand-receptor interactions, especially in terms of how to most meaningfully define a complex chemical stimulus. The challenge of identifying the relevant features of a chemical stimulus is shared by both odorants and drugs. Understanding how the odorant receptors (ORs) of the mammalian peripheral olfactory system functionally classify odorants may thus assist rational drug design, especially among the Class A subtype of G-protein coupled receptors to which the ORs belong. Currently, the functional relationships between odorants are unclear. The relevant dimensions of odorants are not intuitive. While most other primary sensory cortices have "maps" that reflect regularities in their stimuli, piriform cortex has no clear chemotopic map to serve asa guide as to which odorants are "proximal" in chemical space. With no other guide, the default organization of odorants has come from organic chemistry. But olfactory paradoxes suggest that this traditional way of categorizing odorants is insufficient. Some percepts, such as musk, can be elicited by highly divergent chemical structures. Yet highly similar chemical structures, such as the enantiomers of carvone, can sometimes elicit markedly non-overlapping percepts. One problem may be that organic chemistry emphasizes those features that impact synthetic reaction schemes. These features may not have the same relevance in a biological setting. A more biologically-relevant classification of odorants is needed. Medicinal chemistry can help provide this new perspective because it emphasizes a compound's biological function over its chemical form. Some chemical fragment substitutions central to medicinal chemistry generate compounds that appear discrepant and yet these compounds often remain functional at their intended targets, a phenomenon called bioisosterism. We propose to challenge the ability of the diverse ORs to accept three key medicinal chemistry fragment substitutions: exchanging aromatic rings, inverting esters, and bioisosteric substitution of aliphatic scaffolds for a benzen ring. If odorants related by these fragment substitutions elicit similar activity patterns across te OR repertoire, it will support the use of ORs as a naturally diverse platform for drug screening. We will also identify the specific receptors that are activated by the various substitutions in ordr to develop a new, functionally based, classification of the odor receptor family.