Sniffing out pharmacology: interactions of drugs with human olfaction Jo ¨ rn Lo ¨ tsch 1 , Gerd Geisslinger 1 and Thomas Hummel 2 1 pharmazentrum frankfurt and Center for Drug Research, Development and Safety (ZAFES), Institute of Clinical Pharmacology, Goethe-University Hospital, D-60590 Frankfurt am Main, Germany 2 Smell and Taste Clinic, Department of Otorhinolaryngology, Technical University of Dresden Medical School, Fetscherstrasse 74, D-01307 Dresden, Germany Advances in the understanding of the sense of smell have increased awareness of the role of olfaction in human life. Odors are perceived via specific G protein- coupled receptors (GPCRs) with cAMP as the second messenger. Drugs that interact with this signaling cas- cade, such as opioids, cannabinoids and sildenafil, are known to reduce olfactory function. Drugs that are active in the central nervous system (CNS) may also hinder the complex processing of olfactory information to distin- guish, via pattern recognition, thousands of odors from the signals of only 400 distinct olfactory receptors. Many other interactions with drug targets expressed at the olfactory bulb are also likely to occur. However, olfactory drug effects have rarely been explored in con- trolled studies. In the current activities of drug develop- ment and re-purposing, olfaction could become highly important because it can impact significantly upon the enjoyment of food. With an established molecular basis and using available tools, the assessment of olfaction in drug development and approval is advised. The olfactory system Advances in our understanding of the sense of smell [1,2], including Nobel Prize-winning research on odorant recep- tors by Richard Axel and Linda B. Buck [3], have increased awareness of the role of olfaction in human life [4]. Olfac- tion comprises the chemosensory modality dedicated to detecting low concentrations of airborne, volatile chemical substances [5]. It belongs evolutionarily to the most an- cient of senses and is based on, comparatively, the most complex of molecular mechanisms. It comprises of hun- dreds of receptor proteins which enable it to detect and discriminate thousands of odorants [6]. This complex ol- factory network is subjected to many modulating influ- ences related to genetics, gender, age, hormonal status, disease and the surrounding environment. In view of the complexity of the molecular and cortical networks involved in the perception of odors (Figure 1), it is likely that many drugs are olfactory modulators [7] that interfere with the molecular pathways of odor detection and/or the cerebral processing of sensory information. Although human life is often held to be dominated by the visual sense, olfactory stimuli can influence our be- havior in many subtle ways [4]. Olfactory loss in otherwise healthy people can be a cause of suffering because it is associated with reduced enjoyment of food [8]. Damaged olfactory function can impact upon the quality of life of the patient and can greatly affect professionals who rely on their sense of smell. Specifically, professionals particular- ly hit by loss of olfactory function include chefs and perfumers, and, in a broader sense, people working with foods or odorized products (e.g. body care and health care [8]). Therefore, olfactory effects should have a greater importance in drug research and development. In this review we discuss current knowledge about drug effects on human olfaction and examine the possibility of their assessment within the clinical phases of drug develop- ment and approval. Drug effects on olfaction Olfactory drug effects via molecular interactions Odor perception involves a network of molecular pathways concentrated in the olfactory bulb and spread across the brain (Figure 1). More than 900 olfactory genes and pseu- dogenes are spread across the entire human genome with the exception of chromosomes 20 and Y [9] (for details, see the Human Olfactory Data Explorer at http://genome.weiz- mann.ac.il/horde/). The human sense of smell is conferred by the products of approximately 400 functional genes [10] that encode olfactory GPCRs [5] with a seven-transmembrane structure [11]. These receptors allow thousands of volatile chemicals to be perceived as distinct odors. This is conferred by combinatorial coding (i.e. one olfactory receptor recog- nizes multiple odorants and one odorant is recognized by multiple olfactory receptors). Different odorants are recog- nized by different combinations of olfactory receptors [12] such that each molecule generates a unique pattern of activity across the population of receptor cells [5]. Considering this complex perception of odors via 400 interacting receptors, it is likely that odor coding is vul- nerable to drug-induced modifications (Box 1). The G proteins (G s or the olfactory receptor-specific G olf [13]) coupled to the olfactory receptor are linked to adenylyl cyclase (Figure 1, bottom). Receptor activation leads to an intracellular increase in the concentration of cAMP. This Review Corresponding author: Lo ¨tsch, J. (j.loetsch@em.uni-frankfurt.de). 0165-6147/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2012.01.004 Trends in Pharmacological Sciences, April 2012, Vol. 33, No. 4 193