Exploring Linear -, - and -Acetylene Containing Agonists of the Human Olfactory Receptor OR1A1.

Structure-activity relationship studies on olfactory receptors such as OR1A1 enhance an understanding of the molecular mechanism of olfactory perception. Such receptors are considered to be important in regulating physiological roles beyond olfactory perception. Here a series of linearized ketones, alcohols, and a cyclic ether, extended between the oxygen functionality and a terminal -butyl group with either -, -, or -acetylene spacers, was prepared to explore the response of human olfactory receptor OR1A1. The best agonists were -acetylene rods combined with an aryl spacer, including the -acetylene ketones and , as well as the primary aryl--acetylene alcohol and the corresponding secondary alcohol . In the latter case, there was a clear stimulatory preference for the ()- enantiomer. The experimental data were supported by molecular docking of the various ligands on the OR1A1 homology model. Further molecular dynamics simulations revealed atomic details in the OR1A1 binding pocket.