Emerging evidence indicates the orexin system is a key regulator for reward and motivation. It has been demonstrated that orexins, and the orexin-1 receptor in particular, are involved in drug self-administration, drug-associated cue processing, reward, and stress responses during drug abstinence in drug-dependent animals. In contrast to behavioral studies development of OX1 selective ligands has not progressed. Ligand development for the orexin system thus far focused on selective OX2 antagonists and/or dual OX1/OX2 antagonists for sleep disorders such as insomnia. Conversely, only a small number of OX1 selective antagonists have been described and SB-334867 represents the only pharmacological tool that has been employed in evaluating the physiological role of OX1 specific pathways in vivo. Despite its high selectivity, SB- 334867 has undesirable bioavailability (10%) and stability, and high doses of SB-334867 (30mg/kg) have been shown to lead to unwanted side effects (abnormal posture and immobility) that confound interpretation of behavioral experiments. Moreover, small molecule orexin agonists have not been reported and the peptides orexin-A and B remain the only available OX1 agonists for research purposes. Orexin-A and B have relatively low potency at the orexin receptors (~ 50nM) and are either non-selective or slightly OX2 selective. In addition, peptides are susceptible to proteolysis, do not penetrate the blood brain barrier and therefore, are normally directly administrated into the CNS. Taken together, there is an unmet need for selective OX1 agonists and antagonists that will serve as tools to further facilitate understanding of OX1R pharmacology and the critical role orexins play in drug abuse and addiction. In this application, we plan to develop OX1 agonists and antagonists with improved potency, selectivity and pharmacokinetic properties using strategies including rational chemical synthesis, virtual screens and peptidomimetic development.

Public Health Relevance

Emerging evidence suggests that orexin 1 receptors play a critical role in a variety of physiological processes including reward and motivation and therefore, represent a valuable target in medication development for the treatment of drug abuse and addiction. This project plans to develop potent and selective agonists and antagonists for this receptor. These ligands will serve as tools to probe the signaling mechanisms and in vivo function of this receptor and could expedite the ultimate development of novel therapies for the treatment of conditions mediated by orexin signaling including drug abuse and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA032837-02
Application #
8415521
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Singh, Hari
Project Start
2012-02-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$254,132
Indirect Cost
$134,132
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Perrey, David A; Zhang, Yanan (2018) Therapeutics development for addiction: Orexin-1 receptor antagonists. Brain Res :
Perrey, David A; Decker, Ann M; Zhang, Yanan (2018) Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability. ACS Chem Neurosci 9:587-602
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Nguyen, Thuy; Li, Jun-Xu; Thomas, Brian F et al. (2017) Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor. Med Res Rev 37:441-474
Thorn, David A; Qiu, Yanyan; Jia, Shushan et al. (2016) Antinociceptive effects of imidazoline I2 receptor agonists in the formalin test in rats. Behav Pharmacol 27:377-83
Nguyen, Thuy; German, Nadezhda; Decker, Ann M et al. (2015) Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators. Bioorg Med Chem 23:2195-2203
Perrey, David A; Decker, Ann M; Li, Jun-Xu et al. (2015) The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor. Bioorg Med Chem 23:5709-24
Perrey, David A; German, Nadezhda A; Decker, Ann M et al. (2015) Effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the orexin-1 receptor. ACS Chem Neurosci 6:599-614
Jing, Li; Zhang, Yanan; Li, Jun-Xu (2014) Effects of the trace amine associated receptor 1 agonist RO5263397 on abuse-related behavioral indices of methamphetamine in rats. Int J Neuropsychopharmacol 18:
Li, Jun-Xu; Thorn, David A; Qiu, Yanyan et al. (2014) Antihyperalgesic effects of imidazoline I(2) receptor ligands in rat models of inflammatory and neuropathic pain. Br J Pharmacol 171:1580-90

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