Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists

Skudlarek, Jason W.; DiMarco, Christina N.; Babaoglu, Kerim; Roecker, Anthony J.; Bruno, Joseph G.; Pausch, Mark H.; O’Brien, Julie A.; Cabalu, Tamara D.; Stevens, Joanne; Brunner, John; Tannenbaum, Pamela L.; Wuelfing, W. Peter; Garson, Susan L.; Fox, Steven V.; Savitz, Alan T.; Harrell, C. Meacham; Gotter, Anthony L.; Winrow, Christopher J.; Renger, John J.; Kuduk, Scott D.; Coleman, Paul J.

doi:10.1016/j.bmcl.2017.02.012

Cited by 7 publications

(8 citation statements)

References 26 publications

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“…These observations have given way to a substantial interest in developing therapeutic agents that target orexin receptors (Chieffi et al, 2017). To date, there are numerous selective and non-selective orexin receptor antagonists that have been developed (Gotter et al, 2012;Roecker et al, 2016;Skudlarek et al, 2017;Smart et al, 2001;Steiner et al, 2013). Conversely, selective orexin receptor agonists with preclinical or clinical efficacy are scarce (Mieda and Sakurai, 2013;Nagahara et al, 2015;Turku et al, 2017), ultimately leading to the use of orexin peptides as the agonists of choice.…”

Section: Intranasal Administration Of Orexinsmentioning

confidence: 99%

Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction

Calva

Fadel

2020

Brain Research

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Cognitive impairment is a core feature of several neuropsychiatric and neurological disorders, including narcolepsy and age-related dementias. Current pharmacotherapeutic approaches to cognitive enhancement are few in number and limited in efficacy. Thus, novel treatment strategies are needed. The hypothalamic orexin (hypocretin) system, a central integrator of physiological function, plays an important role in modulating cognition. Several single- and dual-orexin receptor antagonists are available for various clinical and preclinical applications, but the paucity of orexin agonists has limited the ability to research their therapeutic potential. To circumvent this hurdle, direct intranasal administration of orexin peptides is being investigated as a prospective treatment for cognitive dysfunction, narcolepsy or other disorders in which deficient orexin signaling has been implicated. Here, we describe the possible mechanisms and therapeutic potential of intranasal orexin delivery. Combined with the behavioral evidence that intranasal orexin-A administration improves cognitive function in narcoleptic and sleep-deprived subjects, our neurochemical studies in young and aged animals highlights the capacity for intranasal orexin administration to improve age-related deficits in neurotransmission. In summary, we highlight prior and original work from our lab and from others that provides a framework for the use of intranasal orexin peptides in treating cognitive dysfunction, especially as it relates to age-related cognitive disorders.

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Section: Intranasal Administration Of Orexinsmentioning

confidence: 99%

Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction

Calva

Fadel

2020

Brain Research

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“…Recently, Skudlarek et al [106] described several series of potential drug candidates with more or less suitable pharmacokinetic properties and receptor affinities ( Figure 5, {31} {32} {33}). Although the general content and motivation remains the treatment of insomnia with antagonists of OX2R, the group provides many suggestions to pharmacophore development of ligands not only for OX2R but also for OX1R.…”

Section: Orexin Receptorsmentioning

confidence: 99%

Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Pissarek¹

2019

WJNS

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Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R; OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among How to cite this paper: Pissarek, M. (2019) Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain. World Journal of Neuroscience, 9, 294-327.

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“…Relative to the numerous orexin receptor antagonists (Smart et al, 2001;Scammell and Winrow, 2011;Mieda and Sakurai, 2013;Steiner et al, 2013;Roecker et al, 2016;Skudlarek et al, 2017;Recourt et al, 2019), development of orexin receptor agonists has been limited (Irukayama-Tomobe et al, 2017;Turku et al, 2017), leading to greater use of native orexin peptides to examine the role of orexins in behavior and cognition. While peripheral administration of the OxA has previously been examined in animal models (John et al, 2000;Fujiki et al, 2003;Deadwyler et al, 2007;Dhuria et al, 2009), several caveats, including peripheral side effects and low bioavailability, limit the potential for this route of administration (Hallschmid and Born, 2008).…”

Section: Introductionmentioning

confidence: 99%

Effects of Intranasal Orexin-A (Hypocretin-1) Administration on Neuronal Activation, Neurochemistry, and Attention in Aged Rats

Calva

Fayyaz

Fadel

2020

Front. Aging Neurosci.

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Cognitive function represents a key determinative factor for independent functioning among the elderly, especially among those with age-related cognitive disorders. However; existing pharmacotherapeutic tactics for treating these disorders provide only modest benefits on cognition. The hypothalamic orexin (hypocretin) system is uniquely positioned, anatomically and functionally, to integrate physiological functions that support proper cognition. The ongoing paucity of orexin receptor agonists has mired the ability to study their potential as cognitive enhancers. Fortunately, intranasal administration of native orexin peptides circumvents this issue and others concerning peptide transport into the central nervous system (CNS). To investigate the ability of intranasal orexin-A (OxA) administration to improve the anatomical, neurochemical, and behavioral substrates of age-related cognitive dysfunction, these studies utilized a rodent model of aging combined with acute intranasal administration of saline or OxA. Here, intranasal OxA increases c-Fos expression in several telencephalic brain regions that mediate important cognitive functions, increases prefrontal cortical acetylcholine efflux, and alters set-shifting-mediated attentional function in rats. Ultimately, these studies provide a framework for the possible mechanisms and therapeutic potential of intranasal OxA in treating age-related cognitive dysfunction.

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Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists

Cited by 7 publications

References 26 publications

Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction

Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction

Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Effects of Intranasal Orexin-A (Hypocretin-1) Administration on Neuronal Activation, Neurochemistry, and Attention in Aged Rats

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