A Medicinal Chemistry Approach to Understanding the Basis of Olfactory Perception

描述(由申请人提供)：将气味的化学结构与其感知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。气味和药物都面临着识别化学刺激的相关特征的挑战。因此，了解哺乳动物外周嗅觉系统的气味受体(ORs)如何对气味进行功能性分类可能有助于合理的药物设计，特别是在ORs所属的A类G蛋白偶联受体中。目前，气味之间的功能关系尚不清楚。气味的相关维度并不直观。虽然大多数其他初级感觉皮质都有反映其刺激规律的“地图”，但梨状皮质没有清晰的化学定位地图来指导化学空间中哪些气味是“接近”的。在没有其他指南的情况下，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。一些感觉，如麝香，可以由高度不同的化学结构引起。然而，高度相似的化学结构，如香芹酮的对映体，有时可以引起明显的互不重叠的感觉。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。这些特征在生物学环境中可能不具有相同的相关性。需要对气味进行更具生物相关性的分类。药物化学可以帮助提供这一新的视角，因为它强调化合物的生物功能而不是其化学形式。一些对药物化学至关重要的化学片段替换产生了看起来不同的化合物，但这些化合物往往在其预定的靶点上保持功能，这种现象被称为生物等构学。我们建议挑战不同的ORs接受三个关键的药物化学片段替换的能力：交换芳环，转化酯，以及用生物等立体取代脂肪族支架来取代苯环。如果与这些片段替换相关的气味在TE或曲目中引起类似的活性模式，它将支持将ORS用作天然多样化的药物筛选平台。我们还将确定由ORDR中的各种替换激活的特定受体，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.