A Medicinal Chemistry Approach to Understanding the Basis of Olfactory Perception

理解嗅觉基础的药物化学方法

基本信息

批准号：
9284272
负责人：
Stuart J Firestein
金额：
$ 33.36万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9284272
关键词：
Acids Alcohols Anatomy Benzene Binding Biological Biological Process Characteristics Chemical Structure Chemicals Classification Classification Scheme Code Complex Detection Dimensions Discrimination Drug Design Electronics Elements Esters Exhibits Family Functional Imaging G-Protein-Coupled Receptors Genes Genome Lead Ligands Link Maps Modality Odorant Receptors Odors Olfactory Pathways Organic Chemistry Pattern Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Preclinical Drug Evaluation Reaction Receptor Gene Research Scheme Sensory Sensory Physiology Signal Transduction Smell Perception Stimulus Structure Techniques Terminology Testing arm base biological systems drug discovery enantiomer functional group functional mimics insight interest novel olfactory receptor piriform cortex preference public health relevance receptive field receptor scaffold sensory cortex success

项目摘要

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.

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的一个长期问题。它强调了阐明配体受体相互作用的需求，尤其是在如何最有意义地定义复杂的化学刺激方面。识别化学刺激的相关特征的挑战是气味剂和药物都共享的。了解哺乳动物周围嗅觉系统的气味受体（ORS）如何在功能上对气味分类可以有助于合理的药物设计，尤其是在ORS所属的G蛋白偶联受体的A类亚型中。当前，气味之间的功能关系尚不清楚。气味的相关尺寸不是直观的。尽管大多数其他原发性感觉皮层具有反映其刺激中规律性的“地图”，但梨状皮层没有明确的趋化图来提供ASA指南，即在化学空间中哪些气味“近端”。没有其他指南，默认的气味组织来自有机化学。但是，嗅觉悖论表明，这种传统的种类气味的方式不足。高度不同的化学结构可以引起一些感知，例如麝香。然而，高度相似的化学结构，例如Carvone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影响合成反应方案的那些特征。这些特征在生物环境中可能没有相同的相关性。需要对生物学的气味分类。药物化学可以帮助提供这种新的观点，因为它强调了化合物在化学形式上的生物学功能。药物化学中心的一些化学片段取代产生了看起来不差异的化合物，但这些化合物通常在其预期靶标中保持功能，这一现象称为生物酶层植物。我们建议挑战各种OR接受三个关键药物化学片段取代的能力：交换芳香环，反相酯和脂肪族脚手架的生物酶取代为苯环。如果这些碎片取代相关的气味会引起跨TE或曲目的类似活动模式，则它将支持ORS用作自然多样化的药物筛查平台。我们还将确定由ORDR中各种取代激活的特定受体，以开发一种新的基于功能的气味受体家族分类。