Olfactory Receptor Antagonism in the OR-I7 Aldehyde Receptor and the Mammalian Olfactory System
type: CreativeWork
description: The detection of smell is initiated when an odorant binds and activates olfactory receptors (ORs) within the nose. Chapter 1 studies the structural requirements for activation of the OR-I7 aldehyde receptor. Octanal is an agonist of the OR-I7 receptor. 4-Ethylcyclohexylacetaldehyde (1.1), with a cyclohexyl ring that locks the C4-C5 bond of octanal in the gauche conformation, was previously found to have higher potency than octanal, suggesting that the OR-I7 receptor prefers the gauche conformation of octanal during activation. However, 1.1 had only been previously tested as a mixture of cis- and trans-isomers, and therefore, it was not possible to determine whether the response of 1.1 was stimulated by either or both of the isomers. In order to distinguish the response of each isomer, the cis and trans compounds were individually synthesized and tested on olfactory sensory neurons (OSNs) that co-express the OR-I7 receptor via calcium imaging. Through this study, we gained insight into the preferred conformation of the C6-C7 bond of octanal for activation of the OR-I7 receptor. Removing the ethyl group of 4-ethylcyclohexylacetaldehyde (1.1) to form cyclohexylacetaldehyde (2.2), transforms the molecule from an activator to an inhibitor of OR-I7. Chapter 2 focuses on antagonism of the rodent OR-I7 aldehyde receptor. Besides 2.2, the response of octanal can be antagonized by several short aliphatic linear and cyclic aldehydes at micromolar concentrations. It was proposed that these antagonists compete with octanal for the binding site via their aldehyde moiety, but fail to activate the receptor due to their shorter chain lengths. The strength of antagonism for this receptor appeared to correlate with the number of aliphatic carbons within 7 Å of the aldehyde when it was modeled in the most extended conformation, but the data set was too small to firmly support this. To further test the possibility, a structure-activity relationship (SAR) study was carried out in which a…
abstract: The detection of smell is initiated when an odorant binds and activates olfactory receptors (ORs) within the nose. Chapter 1 studies the structural requirements for activation of the OR-I7 aldehyde receptor. Octanal is an agonist of the OR-I7 receptor. 4-Ethylcyclohexylacetaldehyde (1.1), with a cyclohexyl ring that locks the C4-C5 bond of octanal in the gauche conformation, was previously found to have higher potency than octanal, suggesting that the OR-I7 receptor prefers the gauche conformation of octanal during activation. However, 1.1 had only been previously tested as a mixture of cis- and trans-isomers, and therefore, it was not possible to determine whether the response of 1.1 was stimulated by either or both of the isomers. In order to distinguish the response of each isomer, the cis and trans compounds were individually synthesized and tested on olfactory sensory neurons (OSNs) that co-express the OR-I7 receptor via calcium imaging. Through this study, we gained insight into the preferred conformation of the C6-C7 bond of octanal for activation of the OR-I7 receptor. Removing the ethyl group of 4-ethylcyclohexylacetaldehyde (1.1) to form cyclohexylacetaldehyde (2.2), transforms the molecule from an activator to an inhibitor of OR-I7. Chapter 2 focuses on antagonism of the rodent OR-I7 aldehyde receptor. Besides 2.2, the response of octanal can be antagonized by several short aliphatic linear and cyclic aldehydes at micromolar concentrations. It was proposed that these antagonists compete with octanal for the binding site via their aldehyde moiety, but fail to activate the receptor due to their shorter chain lengths. The strength of antagonism for this receptor appeared to correlate with the number of aliphatic carbons within 7 Å of the aldehyde when it was modeled in the most extended conformation, but the data set was too small to firmly support this. To further test the possibility, a structure-activity relationship (SAR) study was carried out in which a…
author: Liu, Min Ting
keywords: Chemistry, Organic Chemistry, OR-I7, aldehyde, odorant, olfactory receptor, antagonism
date published: 2017-06-02T07:00:00Z
date modified: 2026-07-24T01:58:49Z
provider: City University of New York - Graduate Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: The Graduate School and University Center of The City University of New York