Development of an orexin-2 receptor selective agonist, [Ala11, d-Leu15]orexin-B

Asahi, Shuichi; Egashira, Shinichiro; Matsuda, Masao; Iwaasa, Hisashi; Kanatani, Akio; Ohkubo, Mitsuru; Ihara, Masaki; Morishima, Hajime

doi:10.1016/s0960-894x(02)00851-x

Cited by 93 publications

(77 citation statements)

References 13 publications

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“…The above results suggest that the excitatory response of cerebellar IN neuron to orexin A and orexin B may be mediated by the OX 2 R. To confirm these results, we further observed the effects of the highly selective OX 2 R agonist [Ala 11 , D-Leu 15 ] orexin B, which showed about a 400-fold selectivity for the OX 2 R over the OX 1 R [20], on the cerebellar IN neuronal spontaneous firing. The agonist mimicked the excitatory effect of orexins on cerebellar IN cells.…”

Section: Effect Of Selective Ox 2 R Agonist [Ala 11 D-leu 15 ] Orexsupporting

confidence: 61%

Orexins Excite Neurons of the Rat Cerebellar Nucleus Interpositus Via Orexin 2 Receptors In Vitro

Zhang

et al. 2009

Cerebellum

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Orexins are newfound hypothalamic neuropeptides implicated in the regulation of feeding behavior, sleep-wakefulness cycle, nociception, addiction, emotions, as well as narcolepsy. However, little is known about roles of orexins in motor control. Therefore, the present study was designed to investigate the effect of orexins on neuronal activity in the cerebellum, an important subcortical center for motor control. In this study, perfusing slices with orexin A (100 nM-1 microM) or orexin B (100 nM-1 microM) both produced neurons in the rat cerebellar interpositus nucleus (IN) a concentration-dependent excitatory response (96/143, 67.1%). Furthermore, both of the excitations induced by orexin A and B were not blocked by the low-Ca(2+)/high-Mg(2+) medium (n = 8), supporting a direct postsynaptic action of the peptides. Highly selective orexin 1 receptor antagonist SB-334867 did not block the excitatory response of cerebellar IN neurons to orexins (n = 22), but [Ala(11), D-Leu(15)] orexin B, a highly selective orexin 2 receptor (OX(2)R) agonist, mimicked the excitatory effect of orexins on the cerebellar neurons (n = 18). These results demonstrate that orexins excite the cerebellar IN neurons through OX(2)R and suggest that the central orexinergic nervous system may actively participate in motor control through its modulation on one of the final outputs of the spinocerebellum.

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Section: Effect Of Selective Ox 2 R Agonist [Ala 11 D-leu 15 ] Orexsupporting

confidence: 61%

Orexins Excite Neurons of the Rat Cerebellar Nucleus Interpositus Via Orexin 2 Receptors In Vitro

Zhang

et al. 2009

Cerebellum

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“…We first showed that the dual OX receptor antagonist TCS1102 and the selective OX2R antagonist EMPA (Malherbe et al, 2009) suppressed the protection provided by OXB, thus clearly implicating OX2R in this effect. In line with this interpretation, the effect of OXB was resistant to the OX1R antagonist SB408124 (Langmead et al, 2004), and was mimicked by [Ala 11 , D-Leu 15 ]OXB, a modified OXB neuropeptide showing a 400-fold selectivity for OX2R over OX1R (Asahi et al, 2003). This conclusion is also in agreement with various reports showing that OXB signals principally through OX2R (Sakurai et al, 1998;Gotter et al, 2012).…”

Section: Survival Promotion Of Dopamine Neurons By Orexinsupporting

confidence: 91%

“…The selective OX1R antagonist SB408124 (1 mM) failed, however, to reduce DA cell rescue by OXB, indicating that only the OX2R subtype was involved in the peptide effect. Consistent with these observations, the selective agonist of OX2R, [Ala 11 , ]OXB (10 nM) [a modified peptide in which the L-leucine residues at positions of 11 and 15 of OXB are replaced by L-alanine and D-leucine (Asahi et al, 2003)], mimicked the rescuing effect of OXB for DA neurons, and this protective effect was prevented by EMPA. Note that the small protective effect of OXA for DA neurons was also abolished by blockade of OX2R with EMPA.…”

Section: Survival Promotion Of Dopamine Neurons By Orexinmentioning

confidence: 57%

The Sleep-Modulating Peptide Orexin-B Protects Midbrain Dopamine Neurons from Degeneration, Alone or in Cooperation with Nicotine

et al. 2014

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To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-proteincoupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype,amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala 11 , ]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of a-bungarotoxin-sensitive (presumably a7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder.

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“…For example, the orexin-B analog [Ala 11 ,D-Leu 15 ]orexin-B was generated by replacing L-leucine residues at positions 11 and 15. These particular substitutions resulted in an enhancement of selectivity toward the OX 2 receptor (compared with the OX 1 receptor) by approximately 400-fold (Asahi et al, 2003). In the same study, a systematic approach to residue replacement revealed that three leucine residues are important for OX-B's selectivity for the OX 2 receptor and determined the minimal peptide sequence required for orexin receptor activation.…”

Section: A Orexin Receptor Agonists/potentiatorsmentioning

confidence: 86%

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

et al. 2012

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Development of an orexin-2 receptor selective agonist, [Ala11, d-Leu15]orexin-B

Cited by 93 publications

References 13 publications

Orexins Excite Neurons of the Rat Cerebellar Nucleus Interpositus Via Orexin 2 Receptors In Vitro

Orexins Excite Neurons of the Rat Cerebellar Nucleus Interpositus Via Orexin 2 Receptors In Vitro

The Sleep-Modulating Peptide Orexin-B Protects Midbrain Dopamine Neurons from Degeneration, Alone or in Cooperation with Nicotine

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

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