Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonists

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Abstract

Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX1R and OX2R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX2R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX2R with a pKi of 8.3, has a pKb of 7.9, and is 600-fold selective for the OX2R over the OX1R.

A series of novel, selective orexin receptor 2 antagonists consisting of substituted 4-phenyl-[1,3]dioxanes is reported (e.g. 9).

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Introduction

In 1998 two research groups, working independently and using different methods, discovered two neuropeptides, orexin A and orexin B.[1], [2] The two neuropeptides, which are processed from the same gene and are produced by neurons in the lateral hypothalamus are also known as the hypocretins.[1], [2] The orexin neuropeptides play a role in a variety of biological functions including the sleep/wake cycle, feeding behavior, regulation of gastric acid secretion, metabolic rate, and blood pressure.[3], [4], [5], [6], [7], [8], [9], [10] Two receptors for orexin A and orexin B were also identified and they are known as orexin 1 (OX1R) and orexin 2 (OX2R).2 While the orexin-2 receptor binds both neuropeptides with similar affinity, the orexin-1 receptor binds orexin A with slightly higher affinity than orexin B. Several reports of antagonists for the orexin-1 receptor have already appeared in the literature and suggest that this receptor is closely related to feeding, metabolism, and digestive function.[11], [12], [13], [14], [15], [16] Recent data suggests that the orexin-2 receptor is associated with the sleep/wake cycle and that mutations to this receptor are related to canine narcolepsy.5 Human narcolepsy appears to be linked to deficient orexin signaling, most likely related to immune ablation of orexinergic neurons in the lateral hypothalamus.[17], [18] Herein we report on a novel series of nonpeptidic, small molecule antagonists for the orexin-2 receptor. These compounds are among the most potent and selective small molecule antagonists for this receptor to date and should prove useful for further elucidating the role of the OX2R receptor.[19], [20], [21], [22]

Section snippets

Chemistry

A high throughput screen (HTS) of our chemical library identified several hits including the novel urea-containing 4-phenyl-[1,3]dioxane, 1, as an antagonist of the human orexin-2 receptor. Compound 1, 1-(2-bromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, as a single enantiomer was also fairly selective for the orexin-2 receptor (pKi OX2R = 7.0, OX1R = 5.7).23 Compound 1 and related analogs were readily synthesized by reacting commercially available isocyanates with amine 2 (

Biological results and discussion

Compounds 1 and 634 were evaluated for biological activity. Determination of receptor binding characteristics of the compounds was accomplished using adherent, cultured recombinant cells, and radioiodinated orexin A.28 In addition, compound antagonism was demonstrated using a functional assay of intracellular Ca++ responses in cells expressing OX2R.29 Agonist binding to orexin receptors elevates the intracellular free calcium ion concentration through the activation of a Gq protein and the

References (31)

  • T Sakurai et al.

    Cell

    (1998)
  • N Takahashi et al.

    Biochem. Biophys. Res. Commun.

    (1999)
  • L Lin et al.

    Cell

    (1999)
  • R.M Chemelli et al.

    Cell

    (1999)
  • A.L Kirchgessner et al.

    Neuron

    (1999)
  • W.K Samson et al.

    Brain Res.

    (1999)
  • A.C Haynes et al.

    Regul. Pept.

    (2000)
  • R.A Porter et al.

    Bioorg. Med. Chem. Lett.

    (2001)
  • E Mignot et al.

    Am. J. Hum. Genet.

    (2001)
  • M Hirose et al.

    Bioorg. Med. Chem. Lett.

    (2003)
  • I.C Nordin et al.

    Tetrahedron Lett.

    (1984)
  • L De Lecea et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1998)
  • S Asahi et al.

    Pept. Sci.

    (1999)
  • T Shirasaka et al.

    Am. J. Physiol.

    (1999)
  • C.T Chen et al.

    Am. J. Physiol.

    (2000)
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