N- Acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: The first orexin-2 receptor selective non-peptidic antagonist

Hirose, Masaaki; Egashira, Shinichiro; Gotô, Yasuhiro; Hashihayata, Takashi; Ohtake, Norikazu; Iwaasa, Hisashi; Hata, Masahiko; Fukami, Tatsuki; Kanatani, Akio; Yamada, Koji

doi:10.1016/j.bmcl.2003.08.038

Cited by 102 publications

(64 citation statements)

References 12 publications

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“…These two antagonists exhibited comparable potencies at their specific receptor subtypes in antagonizing orexin A-induced calcium mobilization in vitro. The pK B values of SB-334867 and TCS OX2 29 to the OX 1 R and OX 2 R, respectively, are 7.3 (Smart et al, 2001) and 7.4 (estimated from the IC 50 value reported by Hirose et al, 2003). The higher potency of TCS OX2 29 compared with SB-334867 in suppressing intracisternal orexin A-induced cardiovascular responses might be caused by the more important role of the OX 2 R in this regard.…”

Section: Discussionmentioning

confidence: 93%

“…To elucidate the contribution of OX 1 R and OX 2 R in orexin-induced depolarizations, we examined the effects of an OX 1 R antagonist, SB-334867 (Smart et al, 2001), and an OX 2 R antagonist, TCS OX2 29 (Hirose et al, 2003), in relation to orexin A-induced depolarizations. The effect of an OX 2 R agonist, [Ala 11 ,D-Leu 15 ]-orexin B, was also examined in RVLM neurons.…”

Section: In Vitro Recording Of Neuronal Activity In the Rvlmmentioning

confidence: 99%

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Orexins Depolarize Rostral Ventrolateral Medulla Neurons and Increase Arterial Pressure and Heart Rate in Rats Mainly via Orexin 2 Receptors

Huang¹,

Dai²,

Lee³

et al. 2010

J Pharmacol Exp Ther

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An injection of orexin A or B into the cisterna magna or the rostral ventrolateral medulla (RVLM), where bulbospinal vasomotor neurons are located, elevated arterial pressure (AP) and heart rate (HR). We examined how orexins affected RVLM neurons to regulate cardiovascular functions by using in vitro recordings of neuronal activity of the RVLM and in vivo measurement of cardiovascular functions in rats. Orexin A and B concentration-dependently depolarized RVLM neurons. At 100 nM, both peptides excited 42% of RVLM neurons. Tetrodotoxin failed to block orexin-induced depolarization. In the presence of N-(2-methyl-6-benzoxazolyl)-NЈ-1, 5-naphthyridin-4-yl urea (SB-334867), an orexin 1 receptor (OX 1 R) antagonist, orexin A depolarized 42% of RVLM neurons with a smaller, but not significantly different, amplitude (4.9 Ϯ 0.8 versus 7.2 Ϯ 1.1 mV). In the presence of (2S)-1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanone hydrochloride (TCS OX2 29), an orexin 2 receptor (OX 2 R) antagonist, orexin A depolarized 25% of RVLM neurons with a significantly smaller amplitude (1.7 Ϯ 0.5 mV). Coapplication of both antagonists completely eliminated orexin A-induced depolarization. An OX 2 R agonist, [Ala 11 ,D-Leu 15 ]-orexin B, concentration-dependently depolarized RVLM neurons. Regarding neuronal phenotypes, orexins depolarized 88% of adrenergic, 43% of nonadrenergic, and 36 to 41% of rhythmically firing RVLM neurons. Intracisternal TCS OX2 29 (3 and 10 nmol) suppressed intracisternal orexin A-induced increases of AP and HR, whereas intracisternal SB-334867 (3 and 10 nmol) had no effect on the orexin A-induced increase of HR but suppressed the orexin A-induced pressor response at 10 nmol. We concluded that orexins directly excite RVLM neurons, which include bulbospinal vasomotor neurons, and regulate cardiovascular function mainly via the OX 2 R, with a smaller contribution from the OX 1 R.Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) increase arterial pressure (AP), heart rate (HR), and sympathetic activity in rats and rabbits, when given by an intracerebroventricular (Samson et al., 1999;Shirasaka et al., 1999;Matsumura et al., 2001), intracisternal (Chen et al., 2000, or intrathecal (Antunes et al., 2001) injection. Regarding the sites of action of orexins in regulating cardiovascular and autonomic functions, the hypothalamic paraventricular nucleus was proposed to be one of the critical sites (reviewed in Kannan et al., 2007). In addition, the medullary structures essential for cardiovascular and autonomic regulation may be responsible for orexin-induced cardiovascular alterations. To explore the role of orexins in medullary control of the AP and HR, Chen et al. (2000) found that an intracisternal injection of orexins induced long-lasting pressor and positive chronotropic responses, and microinjection of orexin A into the rostral ventrolateral medulla (RVLM) caused similar responses in rats. The cardiovascular effects of orexins were also ex...

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Section: Discussionmentioning

confidence: 93%

Section: In Vitro Recording Of Neuronal Activity In the Rvlmmentioning

confidence: 99%

Orexins Depolarize Rostral Ventrolateral Medulla Neurons and Increase Arterial Pressure and Heart Rate in Rats Mainly via Orexin 2 Receptors

Huang¹,

Dai²,

Lee³

et al. 2010

J Pharmacol Exp Ther

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“…Because HEK293 cells were adapted to grow and to be transiently transfected in suspension in spinner flasks, it was possible to produce and prepare large quantities of transfected cells and membranes required for binding studies. (Hirose et al, 2003); and the dual OX 1 /OX 2 antagonists almorexant (BrisbareRoch et al, 2007), Cp-1, Cp-2, and Cp-3 are shown in Fig. 1.…”

Section: Bindingmentioning

confidence: 97%

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists

et al. 2009

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Recent preclinical and clinical research has shown that almorexant promotes sleep in animals and humans without disrupting the sleep architecture. Here, the pharmacology and kinetics of [ 3 H]almorexant binding to human orexin 1 receptor (OX 1 )-and human orexin 2 receptor (OX 2 )-human embryonic kidney 293 membranes were characterized and compared with those of selective OX 1 and OX 2 antagonists, including 1- -408124), and N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). The effect of these antagonists was also examined in vitro on the spontaneous activity of rat ventral tegmental area (VTA) dopaminergic neurons. [3 H]Almorexant bound to a single saturable site on hOX 1 and hOX 2 with high affinity (K d of 1.3 and 0.17 nM, respectively). In Schild analyses using the [ 3 H]inositol phosphates assay, almorexant acted as a competitive antagonist at hOX 1 and as a noncompetitive-like antagonist at hOX 2 . In binding kinetic analyses, [ 3 H]almorexant had fast association and dissociation rates at hOX 1 , whereas it had a fast association rate and a remarkably slow dissociation rate at hOX 2 . In the VTA, orexin-A potentiated the basal firing frequency to 175 Ϯ 17% of control in approximately half of the neurons tested. In the presence of 1 M SB-674042 or SB-408124, the effect of orexin-A was only partially antagonized. However, in the presence of 1 M EMPA or 1 M almorexant, the effect of orexin-A was completely antagonized. In conclusion, almorexant exhibited a noncompetitive and long-lasting pseudo-irreversible mode of antagonism as a result of its very slow rate of dissociation from OX 2 . The electrophysiology data suggest that OX 2 might be more important than OX 1 in mediating the effect of orexin-A on slow-firing of VTA dopaminergic neurons.Orexins (also called hypocretins) belong to a family of neuropeptides that are exclusively synthesized in the neuronal cell bodies of the lateral hypothalamic areas. Orexin-A/hypocretin-1 (33 amino acids) and orexin-B/hypocretin-2 (28 amino acids) are derived from the proteolytic processing of 130 amino acid polypeptide prepro-orexin (de Lecea et al., Article, publication date, and citation information can be found at

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“…The first one to be reported was TCS OX229 [(2S)-1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanone hydrochloride], a tetrahydroisoquinoline with moderate affinity but good selectivity for the OX2R (Hirose et al, 2003). Our evaluation of this molecule revealed poor pharmacokinetic properties and lack of target engagement after systemic administration in rodents (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia

Bonaventure

Shelton

Yun

et al. 2015

J Pharmacol Exp Ther

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Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-, a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/ hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia.

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N- Acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: The first orexin-2 receptor selective non-peptidic antagonist

Cited by 102 publications

References 12 publications

Orexins Depolarize Rostral Ventrolateral Medulla Neurons and Increase Arterial Pressure and Heart Rate in Rats Mainly via Orexin 2 Receptors

Orexins Depolarize Rostral Ventrolateral Medulla Neurons and Increase Arterial Pressure and Heart Rate in Rats Mainly via Orexin 2 Receptors

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists

Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia

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N- Acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: The first orexin-2 receptor selective non-peptidic antagonist

Cited by 102 publications

References 12 publications

Orexins Depolarize Rostral Ventrolateral Medulla Neurons and Increase Arterial Pressure and Heart Rate in Rats Mainly via Orexin 2 Receptors

Orexins Depolarize Rostral Ventrolateral Medulla Neurons and Increase Arterial Pressure and Heart Rate in Rats Mainly via Orexin 2 Receptors

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists

Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia

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Product

Resources

About

Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX₁)/Orexin 2 Receptor (OX₂) Antagonist: Comparison with Selective OX₁ and OX₂ Antagonists