Pharmacological studies of octanal recognition by mammalian odorant receptors

Abstract

The sense of smell is initiated when small molecule odorants bind and activate specific subsets of olfactory receptors (ORs) expressed by olfactory sensory neurons (OSNs). The mammalian nose is able to distinguish thousands of chemical structures through these receptors. The molecular recognition strategies that ORs use to bind and distinguish among different odorants are poorly understood. Here we use drug design techniques to probe olfactory molecular recognition using a model odorant-receptor pair in vivo. Specifically, octanal analogs were designed and synthesized to probe the steric and electronic requirements of octanal recognition by the aldehyde-specific rat OR-I7 in OSNs.

The testing of conformationally restricted octanal analogs (Chapter 1) indicates that OR-I7 distinguishes among aliphatic aldehydes according to their length and carbon chain conformation. A gauche conformation between C₄ and C₅ is proposed to be necessary to fill a small hydrophobic binding pocket 7 to 8 Å from the receptor-bound aldehyde with octanal's hydrophobic tail. In addition, small cycloalkyl groups at the tail enhance activation potency, leading to one analog that is more potent than octanal.

Several pairs of stereoisomers and analogs derived from cyclohexylacetaldehyde (Chapter 2) were also designed and synthesized to study the active conformation of octanal at C₄-C₅ and C₆-C₇ positions.

To study the possibility that OR-I7 and other aldehyde-specific olfactory receptors recognize, not the aldehyde, but its gem-diol hydrate, difluorooctanal, dimethyloctanal, octanol and octanal and were screened against more than 1,000 OSNs in vivo. 87 octanal-responsive OSNs were found. The response profiles of these cells support the hypothesis that for some ORs aldehydes function, by analogy to prodrugs, as pro-odorants, or "prodorants." The volatility of the aldehyde allows delivery to nasal mucous, where the aldehyde form is in equilibrium with the gem-diol, a form that has much richer H-bonding capacity.

Through these studies, some molecular recognition details of octanal by ORs were obtained, which could contribute to the understanding of general odorant-receptor recognition strategy.