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Dual'' Orexin Receptor Antagonists at OX1R and OX2R Orexin Receptors

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Dual'' Orexin Receptor Antagonists at OX1R and OX2R Orexin Receptors ORIGINAL RESEARCH ARTICLE published: 03 December 2013 doi: 10.3389/fnins.2013.00230 Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors Gabrielle E. Callander 1,2, Morenike Olorunda 3, Dominique Monna 3, Edi Schuepbach 3, Daniel Langenegger 3, Claudia Betschart 4, Samuel Hintermann 4, Dirk Behnke 4, Simona Cotesta 4, Markus Fendt 3†, Grit Laue 5, Silvio Ofner 4, Emmanuelle Briard 4, Christine E. Gee 3,6, Laura H. Jacobson 3† and Daniel Hoyer 1,2,3* 1 Department of Pharmacology and Therapeutics, Faculty of Medicine, Dentistry and Health Sciences, School of Medicine, The University of Melbourne, Parkville, VIC, Australia 2 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia 3 Department of Neuroscience, Novartis Institutes for Biomedical Research, Basel, Switzerland 4 Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland 5 Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland 6 Centre for Neurobiology Hamburg, Institute for Synaptic Physiology, Hamburg, Germany Edited by: Orexin receptor antagonists represent attractive targets for the development of drugs Christopher J. Winrow, Merck, USA for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings Reviewed by: and thorough investigations of pharmacokinetics and pharmacodynamics can predict Anthony J. Hannan, University of contributing factors such as duration of action and undesirable effects. To this end, we Melbourne, Australia Zoë Bichler, National Neuroscience studied the interactions between various “dual” orexin receptor antagonists and the Institute, Singapore orexin receptors, OX1RandOX2R, over time using saturation and competition radioligand 3 *Correspondence: binding with [ H]-BBAC ((S)-N-([1,1 -biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2- Daniel Hoyer, Department of yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds Pharmacology and Therapeutics, were investigated in cells expressing human, mouse and rat OX RandOX R using FLIPR® Faculty of Medicine, Dentistry and 1 2 Health Sciences, School of assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium Medicine, The University of very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to Melbourne, Parkville, VIC 3010, reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the Australia selective OX R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9- e-mail: [email protected] 2 diazaspiro[5.5]undecan-1-one) bind rapidly and reach equilibrium very quickly in binding †Present address: Markus Fendt, Institute for and/or functional assays. Overall, the “dual” antagonists tested here tend to be rather Pharmacology and Toxicology, unselective under non-equilibrium conditions and reach equilibrium very slowly. Once Otto-von-Guericke University equilibrium is reached, each ligand demonstrates a selectivity profile that is however, Magdeburg, Magdeburg, Germany; distinct from the non-equilibrium condition. The slow kinetics of the “dual” antagonists Laura H. Jacobson, The Florey Institute of Neuroscience and tested suggest that in vitro receptor occupancy may be longer lasting than would be Mental Health, The University of predicted. This raises questions as to whether pharmacokinetic studies measuring plasma Melbourne, Parkville, Australia or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo. Keywords: orexin receptor antagonists, dual orexin receptor antagonists, kinetics, radioligands 2+ INTRODUCTION receptors can couple to Gq and mobilize intracellular Ca via Theorexinreceptors,OX1RandOX2R, were deorphanised in activation of phospholipase C (Sakurai et al., 1998), whilst OX2R 1998, when two independent teams identified the peptides orexin can also couple Gi/Go and inhibit cAMP production via inhibi- AandorexinB(de Lecea et al., 1998; Sakurai et al., 1998). tion of adenylate cyclase (Zhu et al., 2003). In non-neuronal cells OX1RandOX2R are G protein-coupled receptors that share 64% OX2R is capable of extracellular signal-regulated kinase activation amino acid sequence identity in humans and are highly conserved via Gs,Gq,andGi (Tang et al., 2008). In competition radioli- between species (de Lecea et al., 1998; Sakurai et al., 1998). Both gand binding OX1R has a 10–100 fold higher affinity for orexin A (20 nM) than for orexin B (250 nM), whereas OX2R binds both Abbreviations: 5-HT, serotonin; BBAC, (S)-N-([1,1-biphenyl]-2-yl)-1-(2-((1- orexin peptides with similar affinity (Sakurai et al., 1998). methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide; BSA, Orexin is exclusively expressed by orexin producing neu- Bovine Serum Albumin; cAMP, cyclic AMP; CHO, Chinese Hamster Ovary; DMEM, Dulbecco’s Modified Eagle’s Medium; F12, Ham’s F12 nutrients mix- rons within the perifornical nucleus, the dorsomedial hypotha- ture; FDA, Federal Drug Administration of the United States Department of lamic nucleus, and the dorsal and lateral hypothalamic areas Health and Human Services; FLIPR®, FLuorescent Imaging Plate Reader; GABA, (Peyron et al., 1998). Orexin producing neurons are limited γ -aminobutyric acid; HEK, Human Embryonic Kidney; IPSU, 2-((1H-Indol-3- to a few thousand in rodents, whereas in humans there are yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one; KO, Knock Out; NSB, Non-specific Binding; OX1R, orexin receptor 1; OX2R, orexin approximately 30,000–70,000. These neurons have both ascend- receptor 2; REM, Rapid Eye Movement (sleep state). ing and descending projections with dense projections to key www.frontiersin.org December 2013 | Volume 7 | Article 230 | 1 Callander et al. Kinetics of orexin receptor antagonists nuclei of the ascending arousal system such as the adrenergic amnesia, impaired balance and sleep behaviors such as sleep locus coeruleus, the serotonergic dorsal raphe, and the histamin- walking and eating (Buysse, 2013). ergic tuberomammillary nucleus. These same regions also receive Anumberoforexinreceptorantagonistshavebeendevel- inhibitory projections from the ventrolateral preoptic area, which oped that are expected to have advantages over classic sleep promote sleep (Sherin et al., 1998). promoting drugs (see Uslaner et al., 2013). These have been Theorexinreceptorsarewidelydistributedinthebrainina reported as “dual” antagonists as they have apparently similar pattern consistent with orexin neuron projections (Trivedi et al., affinities for both OX1RandOX2R(Roecker and Coleman, 2008; 1998; Marcus et al., 2001). Although the expression patterns of the Scammell and Winrow, 2011). Almorexant was the first com- receptors are largely overlapping, OX1R is selectively expressed pound for which clinical data was reported in volunteers and in the locus coeruleus and OX2R is expressed in the tubero- patients (Brisbare-Roch et al., 2007; Malherbe et al., 2009; Owen mammillary nucleus. The broad distribution of the orexin system et al., 2009) followed closely by SB-649868 (also known as GW throughout the cortex, hippocampus, thalamic, and hypothala- 649868) (Bettica et al., 2009a,b, 2012a,b,c), suvorexant, the most mic nuclei suggests it may modulate a variety of functions includ- advanced antagonist that has successfully completed phase III ing arousal, appetite, metabolism, reward, stress, and autonomic clinical trials (Cox et al., 2010; Winrow et al., 2011; Connor et al., function (Scammell and Winrow, 2011; Gotter et al., 2012). 2012; Herring et al., 2012b; Ivgy-May et al., 2012)andfilorexant Although orexin was originally named for its role in feed- (Coleman et al., 2012; Winrow et al., 2012). Also in this issue, ing behavior (Sakurai et al., 1998), the link between energy we present our characterization of IPSU (Hoyer et al., 2013), an homeostasis and sleep/wakefulness is increasingly recognized orally bioavailable, brain penetrant OX2R antagonist, on sleep (Yamanaka et al., 2003) and it is clear that the orexin system architecture in mice. is crucial for the stability of wake and sleep states (Sakurai, During the characterization of orexin receptor antagonists, we 2007). The orexin system was first linked to the sleep disorder and others (Malherbe et al., 2010; Mang et al., 2012; Morairty narcolepsy: a mutation in the OX2R gene was found to cause et al., 2012) have noticed that almorexant has peculiar kinetic canine narcolepsy (Lin et al., 1999) and the knockout (KO) of features, in particular a very slow dissociation rate constant orexin peptides in mice also resulted in narcolepsy with cata- especially at OX2R. Such features may be clinically relevant as plexy (Chemelli et al., 1999). Indeed, several orexin system KO they influence duration of action and potential for side effects. and transgenic models exhibit sleep abnormalities reminiscent of Therefore, we performed kinetic studies on the dual orexin recep- narcolepsy (Chemelli et al., 1999; Hara et al., 2001a,b; Willie et al., tor antagonists listed above in comparison with BBAC (Figure 1) 2003; Beuckmann et al., 2004). The absence of orexin neurons and/or IPSU in radioligand binding and signaling studies at both or peptides and the double receptor KO mouse models reca- OX1RandOX2R. pitulate the human narcoleptic symptoms, with narcoleptic and cataplectic phenotypes, whereas single orexin receptor KO mice MATERIALS AND
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