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Paul J. Coleman - One of the best experts on this subject based on the ideXlab platform.
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Chapter Six - Orexin Receptor Antagonists in Development for Insomnia and CNS Disorders
Annual Reports in Medicinal Chemistry, 2020Co-Authors: Scott D. Kuduk, Christopher J Winrow, Paul J. ColemanAbstract:Abstract Since the first identification of the key role of the Orexin signaling pathway in regulating sleep/wake and vigilance, a number of drug candidates have entered clinical development targeting the Orexin Receptors. Among them, suvorexant has been reported to be filed as an New Drug Application (NDA) with the Federal Drug Administration (FDA) in 2012 with the potential to be the first approved Orexin Receptor antagonist for the treatment of insomnia. A number of additional dual antagonists as well as selective antagonists have been identified to further elucidate the roles of each individual subtype. Beyond sleep disorders, targeting Orexin Receptors may offer the potential for other therapeutic indications such as migraine, neuropathic pain, depression, anxiety, and addiction.
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Orexin Receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Paul J. Coleman, Jyrki P Kukkonen, Anthony L Gotter, John J Renger, Luis De Lecea, Jim J. Hagan, Rebecca Hills, Thomas S. Kilduff, Rod A. Porter, Jerome M. SiegelAbstract:Orexin Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin Receptors [39]) are activated by the endogenous polypeptides Orexin-A and Orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproOrexin or Orexin precursor, by proteolytic cleavage and some typical peptide modifications [102]. Currently the only Orexin Receptor ligand in clinical use is suvorexant, which is used as a hypnotic. Orexin Receptor crystal structures have been solved [124, 123].
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the discovery of suvorexant the first Orexin Receptor drug for insomnia
Annual Review of Pharmacology and Toxicology, 2017Co-Authors: Paul J. Coleman, Christopher J Winrow, Anthony L Gotter, Joseph W Herring, John J RengerAbstract:Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABAA) Receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of Orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, Orexin antagonism emerged as an alternative approach to attenuate Orexin-induced wakefulness more selectively. Dual Orexin Receptor antagonists (DORAs) block the activity of Orexin 1 and 2 Receptors to both reduce the threshold to transition into sleep and attenuate Orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABAA Receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage–specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinc...
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Orexin Receptor antagonists new therapeutic agents for the treatment of insomnia
Journal of Medicinal Chemistry, 2016Co-Authors: Anthony J. Roecker, Paul J. ColemanAbstract:Since its discovery in 1998, the Orexin system, composed of two G-protein coupled Receptors, Orexins 1 and 2, and two neuropeptide agonists, Orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the Orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse Orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual Orexin Receptor antagonist for the treatment of insomnia.
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international union of basic and clinical pharmacology lxxxvi Orexin Receptor function nomenclature and pharmacology
Pharmacological Reviews, 2012Co-Authors: Anthony L Gotter, Paul J. Coleman, John J Renger, Andrea L Webber, Christopher J WinrowAbstract:Orexin signaling is essential for normal regulation of arousal and behavioral state control and represents an attractive target for therapeutics combating insomnia. Alternatively termed hypocretins, these neuropeptides were named to reflect sequence similarity to incretins and their potential to promote feeding. Current nomenclature reflects these molecular and biochemical discovery approaches in which HCRT , HCRTR1 , and HCRTR2 genes encode prepro-Orexin, the Orexin 1 Receptor (OX1) and the Orexin 2 Receptor (OX2)—gene names designated by the Human Genome Organization and Receptor names designated by the International Union of Basic and Clinical Pharmacology. Orexinergic neurons are most active during wakefulness and fall silent during inactive periods, a prolonged disruption in signaling most profoundly resulting in hypersomnia and narcolepsy. Hcrtr2 mutations underlie the etiology of canine narcolepsy, deficiencies in Orexin-producing neurons are observed in the human disorder, and ablation of mouse Orexin neurons or the Hcrt gene results in a narcolepsy-cataplexy phenotype. The development of Orexin Receptor antagonists and genetic models targeting components of the Orexin pathway have elucidated the OX2 Receptor-specific role in histamine-mediated arousal and the contribution of both Receptors in brainstem pathways involved in vigilance state gating. Orexin Receptor antagonists of varying specificity uncovered additional roles beyond sleep and feeding that include addiction, depression, anxiety, and potential influences on peripheral physiology. Combined genetic and pharmacological approaches indicate that Orexin signaling may represent a confluence of sleep, feeding, and reward pathways. Selective Orexin Receptor antagonism takes advantage of these properties toward the development of novel insomnia therapeutics.
Susan L Garson - One of the best experts on this subject based on the ideXlab platform.
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The duration of sleep promoting efficacy by dual Orexin Receptor antagonists is dependent upon Receptor occupancy threshold
BMC Neuroscience, 2013Co-Authors: Anthony L Gotter, Christopher J Winrow, Susan L Garson, Joanne Stevens, Joseph Brunner, Charles M Harrell, Alan T Savitz, Jacquelyn Binns, Mark Stiteler, Pamela L. TannenbaumAbstract:Background Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, Receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound’s mechanism of action. Results Dual Orexin Receptor antagonists (DORAs) block the arousal-promoting activity of Orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous Orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to Orexin 2 Receptor (OX_2R) occupancies in the range of 65 to 80%. In rats, the time course of OX_2R occupancy was dependent upon Receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes. Conclusion The higher levels of Receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold Receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.
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Orexin Receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition
Science Translational Medicine, 2013Co-Authors: Jason M Uslaner, Susan L Garson, Joanne Stevens, Donnie M Eddins, Xiaohai Wang, Alan T Savitz, Jacquelyn Binns, Christopher E Cannon, Robert Hodgson, Mark R BowlbyAbstract:Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABA A )–positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual Orexin 1 and 2 Receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual Orexin Receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound’s minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity–regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABA A -positive allosteric modulators currently in use.
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discovery of 2r 5r 5 5 fluoropyridin 2 yl oxy methyl 2 methylpiperidin 1 yl 5 methyl 2 pyrimidin 2 yl phenyl methanone mk 6096 a dual Orexin Receptor antagonist with potent sleep promoting properties
ChemMedChem, 2012Co-Authors: Paul J. Coleman, Scott M Doran, John D. Schreier, Georgia B. Mcgaughey, Michael J. Bogusky, Michael J Breslin, David B Whitman, Rodney A Bednar, Wei Lemaire, Susan L GarsonAbstract:Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and Orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual Orexin 1 and Orexin 2 Receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent Orexin Receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.
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promotion of sleep by suvorexant a novel dual Orexin Receptor antagonist
Journal of Neurogenetics, 2011Co-Authors: Christopher J Winrow, Duane R Reiss, Scott M Doran, Susan L Garson, Anthony L Gotter, Joanne Stevens, Pamela L. Tannenbaum, Michael J Breslin, Charles M Harrell, Paul J. ColemanAbstract:Abstract: Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two Receptors respond to Orexin signaling, Orexin 1 Receptor (OX1R) and Orexin 2 Receptor (OX2R) with partially overlapping nervous system distributions. Genetic studies suggest Orexin Receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX1R and OX2R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX2R found nearly full Receptor occupancy (>90%) at plasma exposures of 1.1 μM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes ...
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discovery of 3 9 diazabicyclo 4 2 1 nonanes as potent dual Orexin Receptor antagonists with sleep promoting activity in the rat
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Paul J. Coleman, Anthony J. Roecker, Duane R Reiss, Scott M Doran, John D. Schreier, Georgia B. Mcgaughey, George D. Hartman, Swati P Mercer, Meacham C Harrell, Susan L GarsonAbstract:Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin Receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
Georgia B. Mcgaughey - One of the best experts on this subject based on the ideXlab platform.
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discovery of 2r 5r 5 5 fluoropyridin 2 yl oxy methyl 2 methylpiperidin 1 yl 5 methyl 2 pyrimidin 2 yl phenyl methanone mk 6096 a dual Orexin Receptor antagonist with potent sleep promoting properties
ChemMedChem, 2012Co-Authors: Paul J. Coleman, Scott M Doran, John D. Schreier, Georgia B. Mcgaughey, Michael J. Bogusky, Michael J Breslin, David B Whitman, Rodney A Bednar, Wei Lemaire, Susan L GarsonAbstract:Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and Orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual Orexin 1 and Orexin 2 Receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent Orexin Receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.
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discovery of 3 9 diazabicyclo 4 2 1 nonanes as potent dual Orexin Receptor antagonists with sleep promoting activity in the rat
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Paul J. Coleman, Anthony J. Roecker, Duane R Reiss, Scott M Doran, John D. Schreier, Georgia B. Mcgaughey, George D. Hartman, Swati P Mercer, Meacham C Harrell, Susan L GarsonAbstract:Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin Receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
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discovery of the dual Orexin Receptor antagonist 7r 4 5 chloro 1 3 benzoxazol 2 yl 7 methyl 1 4 diazepan 1 yl 5 methyl 2 2h 1 2 3 triazol 2 yl phenyl methanone mk 4305 for the treatment of insomnia
Journal of Medicinal Chemistry, 2010Co-Authors: Michael J Breslin, Anthony J. Roecker, John D. Schreier, Georgia B. Mcgaughey, Michael J. Bogusky, Swati P Mercer, David B Whitman, Rodney A Bednar, Wei Lemaire, Joseph G. BrunoAbstract:Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides Orexins A and B by design of Orexin Receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane Orexin Receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual Orexin Receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
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Design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as potent Orexin Receptor antagonists.
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Paul J. Coleman, Duane R Reiss, John D. Schreier, Georgia B. Mcgaughey, Michael J. Bogusky, George D. Hartman, Richard G. Ball, C. Meacham Harrell, Thomayant PrueksaritanontAbstract:Abstract Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of Orexin Receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as Orexin Receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.
John D. Schreier - One of the best experts on this subject based on the ideXlab platform.
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discovery of 2r 5r 5 5 fluoropyridin 2 yl oxy methyl 2 methylpiperidin 1 yl 5 methyl 2 pyrimidin 2 yl phenyl methanone mk 6096 a dual Orexin Receptor antagonist with potent sleep promoting properties
ChemMedChem, 2012Co-Authors: Paul J. Coleman, Scott M Doran, John D. Schreier, Georgia B. Mcgaughey, Michael J. Bogusky, Michael J Breslin, David B Whitman, Rodney A Bednar, Wei Lemaire, Susan L GarsonAbstract:Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and Orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual Orexin 1 and Orexin 2 Receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent Orexin Receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.
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discovery of 3 9 diazabicyclo 4 2 1 nonanes as potent dual Orexin Receptor antagonists with sleep promoting activity in the rat
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Paul J. Coleman, Anthony J. Roecker, Duane R Reiss, Scott M Doran, John D. Schreier, Georgia B. Mcgaughey, George D. Hartman, Swati P Mercer, Meacham C Harrell, Susan L GarsonAbstract:Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin Receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
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discovery of the dual Orexin Receptor antagonist 7r 4 5 chloro 1 3 benzoxazol 2 yl 7 methyl 1 4 diazepan 1 yl 5 methyl 2 2h 1 2 3 triazol 2 yl phenyl methanone mk 4305 for the treatment of insomnia
Journal of Medicinal Chemistry, 2010Co-Authors: Michael J Breslin, Anthony J. Roecker, John D. Schreier, Georgia B. Mcgaughey, Michael J. Bogusky, Swati P Mercer, David B Whitman, Rodney A Bednar, Wei Lemaire, Joseph G. BrunoAbstract:Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides Orexins A and B by design of Orexin Receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane Orexin Receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual Orexin Receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
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Design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as potent Orexin Receptor antagonists.
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Paul J. Coleman, Duane R Reiss, John D. Schreier, Georgia B. Mcgaughey, Michael J. Bogusky, George D. Hartman, Richard G. Ball, C. Meacham Harrell, Thomayant PrueksaritanontAbstract:Abstract Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of Orexin Receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as Orexin Receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.
Jyrki P Kukkonen - One of the best experts on this subject based on the ideXlab platform.
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Orexin Receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Paul J. Coleman, Jyrki P Kukkonen, Anthony L Gotter, John J Renger, Luis De Lecea, Jim J. Hagan, Rebecca Hills, Thomas S. Kilduff, Rod A. Porter, Jerome M. SiegelAbstract:Orexin Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin Receptors [39]) are activated by the endogenous polypeptides Orexin-A and Orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproOrexin or Orexin precursor, by proteolytic cleavage and some typical peptide modifications [102]. Currently the only Orexin Receptor ligand in clinical use is suvorexant, which is used as a hypnotic. Orexin Receptor crystal structures have been solved [124, 123].
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Structure-activity relationships of 1-benzoylazulenes at the OX1 and OX2 Orexin Receptors
ChemMedChem, 2019Co-Authors: Ainoleena Turku, Jyrki P Kukkonen, Teppo O. Leino, Lasse Karhu, Jari Yli-kauhaluoma, Erik A. A. Wallen, Henri XhaardAbstract:We previously demonstrated the potential of di- or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the Orexin Receptors. In this study we investigated 27 1-benzoylazulene derivatives, uncovering seven potentiators of the Orexin response on OX1 and two weak dual Orexin Receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure-activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen-bond acceptors (1-position, benzoyl; 6-position, carboxyl/ester) within 7-8 Å of each other; a third acceptor at the 3-position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the Orexin Receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.
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Orexin Receptor multimerization versus functional interactions neuropharmacological implications for opioid and cannabinoid signalling and pharmacogenetics
Pharmaceuticals policy and law, 2017Co-Authors: Miles D Thompson, Takeshi Sakurai, Innocenzo Rainero, Jyrki P KukkonenAbstract:Orexins/hypocretins are neuropeptides formed by proteolytic cleavage of a precursor peptide, which are produced by neurons found in the lateral hypothalamus. The G protein-coupled Receptors (GPCRs) for these ligands, the OX1 and OX2 Orexin Receptors, are more widely expressed throughout the central nervous system. The Orexin/hypocretin system has been implicated in many pathways, and its dysregulation is under investigation in a number of diseases. Disorders in which Orexinergic mechanisms are being investigated include narcolepsy, idiopathic sleep disorders, cluster headache and migraine. Human narcolepsy has been associated with Orexin deficiency; however, it has only rarely been attributed to mutations in the gene encoding the precursor peptide. While gene variations within the canine OX2 gene hcrtr2 have been directly linked with narcolepsy, the majority of human Orexin Receptor variants are weakly associated with diseases (the idiopathic sleep disorders, cluster headache and polydipsia-hyponatremia in schizophrenia) or are of potential pharmacogenetic significance. Evidence for functional and/or heterodimerization between wild-type variant Orexin Receptors and opioid and cannabinoid Receptors is discussed in the context of its relevance to depression and epilepsy.
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Orexin Receptor agonist Yan 7874 is a weak agonist of Orexin/hypocretin Receptors and shows Orexin Receptor-independent cytotoxicity.
PLOS ONE, 2017Co-Authors: Ainoleena Turku, Maiju Rinne, Gustav Boije Af Gennäs, Henri Xhaard, Dan Lindholm, Jyrki P KukkonenAbstract:Two promising lead structures of small molecular Orexin Receptor agonist have been reported, but without detailed analyses of the pharmacological properties. One of them, 1-(3,4-dichlorophenyl)-2-[2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl]ethan-1-ol (Yan 7874), is commercially available, and we set out to analyze its properties. As test system we utilized human OX1 and OX2 Orexin Receptor-expressing Chinese hamster ovary (CHO) K1 cells as well as control CHO-K1 and neuro-2a neuroblastoma cells. Gq-coupling was assessed by measurement of intracellular Ca2+ and phospholipase C activity, and the coupling to Gi and Gs by adenylyl cyclase inhibition and stimulation, respectively. At concentrations above 1 μM, strong Ca2+ and low phospholipase C responses to Yan 7874 were observed in both OX1- and OX2-expressing cells. However, a major fraction of the response was not mediated by Orexin Receptors, as determined utilizing the non-selective Orexin Receptor antagonist N-biphenyl-2-yl-1-{[(1-methyl-1H-benzimidazol-2-yl)sulfanyl]acetyl}-L-prolinamide (TCS 1102) as well as control CHO-K1 cells. Yan 7874 did not produce any specific adenylyl cyclase response. Some experiments suggested an effect on cell viability by Yan 7874, and we thus analyzed this. Within a few hours of exposure, Yan 7874 markedly changed cell morphology (shrunken, rich in vacuoles), reduced growth, promoted cell detachment, and induced necrotic cell death. The effect was equal in cells expressing Orexin Receptors or not. Thus, Yan 7874 is a weak partial agonist of Orexin Receptors. It also displays strong off-target effects in the same concentration range, culminating in necrotic cell demise. This makes Yan 7874 unsuitable as Orexin Receptor agonist.
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Multiple signaling pathways of Orexin Receptors
SpringerPlus, 2015Co-Authors: Jyrki P KukkonenAbstract:Orexin/hypocretin peptides are central for the regulation of the sleep/arousal states, and have, in addition, a role in the regulation of e.g. metabolism, addiction, stress response and pain gating. Orexin responses are mediated by G-protein-coupled OX1 and OX2 Orexin Receptors. Orexin signaling (in different cell types) is very versatile, ranging from excitation to induction of cell death. Orexin Receptor coupling is promiscuous, engaging members of at least three different families of G-proteins, namely Gi, Gs and Gq, and some non-G-protein mediators as well. Preferred G-protein-coupling of the Receptors appears different in different tissues, but the mechanism determining this are unknown. The primary signal transducers of Orexin Receptors very effectively activate phosholipase cascades, including PLA2, PLC and PLD, and also PLC-diacylglycerol lipase-mediated endocannabinoid generation. These cascades may play a significant role in the regulation of K+ and non-selective cation channels, which are the effectors for the Orexin-mediated neuronal excitation. In some cell types, Orexin Receptor stimulation induces programmed cell death. Some different mechanisms for his have been proposed, but the picture is still incomplete. Orexin Receptors have been a target for multiple drug discovery projects. Main focus has been on the antagonists, with insomnia as the indication. For agonist drugs there are some ongoing smaller academic and semi-academic projects. Use of Orexin Receptor agonists is suggested to be beneficial in narcolepsy (as peptide replacement therapy) and putatively in other sleep/wakefulness disturbances, metabolic disorders and cancer.