ECRO XIX Trieste: “Identification of antagonists of OR7D4 that neutralizes the perception of androstenone”

Odorant receptors (OR) constitute the largest family of GPCR dedicated to a single function: perception of odors. The development of OR functional assays based on heterologous expression systems has paved the way for the identification of OR ligands including agonists, antagonists, positive or negative allosteric modulators. The antagonist search applied to OR can lead to the identification of compounds that hamper the perception of an odorant triggering a target OR. So far, few reliable experimental demonstrations support this concept. Here, we present the first reported discovery of antagonists for OR7D4 that allows the perception of androstenone and androstadienone. Using the functional assay platform developed at ChemCom, more than 4000 compounds spread in different libraries of potential antagonists were screened on the human OR7D4. The ethyl 4-benzylidene-2-methyldec-2-enoate popped up as a hit and was confirmed to avoid the receptor activation by its agonists. The antagonist specificity on OR7D4 was demonstrated by its innocuity on other olfactory receptors. A structure-activity relationship study, led to determine the optimal antagonist scaffold, showed that reducing the main carbon chain after the benzylidene insertion decreases the antagonist potency. Replacing the ester moiety by ketones or amides doesn’t affect the potency. In contrast, substitutions by other functional groups result in a decreased antagonist efficiency. None of the tested substitutions on the aromatic ring improved this activity. Finally, sensory assessments of some potent in vitro antagonists were performed on a limited panel of androstenone smellers. Two of the tested compounds that possess a faint intrinsic smell performed well as odor blocker of this sweaty molecule. Beyond the identification of efficient neutralizers of the malodor of a sweat compound, our study demonstrates the feasibility of the in vitro approach for finding new modulators of olfactory perception.

Veithen Alex, Philippeau Magali, Huysseune Sandra, Quesnel Yannick

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