Substituted Tetrahydroisoquinolines As Selective Antagonists for the Orexin 1 Receptor

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Aug 15

PMID 23941044

Citations 14

Authors

David A Perrey

Nadezhda A German

Brian P Gilmour

Jun-Xu Li

Danni L Harris

Brian F Thomas

Yanan Zhang

Affiliations

Soon will be listed here.

Abstract

Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and a preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats.

Citing Articles

Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine.

Black E, Samels S, Xu W, Barson J, Bass C, Kortagere S Addict Neurosci. 2023; 7.

PMID: 37854172 PMC: 10583964. DOI: 10.1016/j.addicn.2023.100104.

An Update on Assessment, Therapeutic Management, and Patents on Insomnia.

Porwal A, Yadav Y, Pathak K, Yadav R Biomed Res Int. 2021; 2021:6068952.

PMID: 34708126 PMC: 8545506. DOI: 10.1155/2021/6068952.

Berbamine Analogs Exhibit Differential Protective Effects From Aminoglycoside-Induced Hair Cell Death.

Hudson A, Lockard G, Namjoshi O, Wilson J, Kindt K, Blough B Front Cell Neurosci. 2020; 14:234.

PMID: 32848624 PMC: 7403526. DOI: 10.3389/fncel.2020.00234.

Therapeutics development for addiction: Orexin-1 receptor antagonists.

Perrey D, Zhang Y Brain Res. 2018; 1731:145922.

PMID: 30148984 PMC: 6387867. DOI: 10.1016/j.brainres.2018.08.025.

Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability.

Perrey D, Decker A, Zhang Y ACS Chem Neurosci. 2017; 9(3):587-602.

PMID: 29129052 PMC: 6002953. DOI: 10.1021/acschemneuro.7b00402.

References

Sakurai T . Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev. 2005; 9(4):231-41. DOI: 10.1016/j.smrv.2004.07.007. View

Kilduff T, Peyron C . The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci. 2000; 23(8):359-65. DOI: 10.1016/s0166-2236(00)01594-0. View

de Lecea L, Kilduff T, Peyron C, Gao X, Foye P, Danielson P . The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A. 1998; 95(1):322-7. PMC: 18213. DOI: 10.1073/pnas.95.1.322. View

Hara J, Yanagisawa M, Sakurai T . Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions. Neurosci Lett. 2005; 380(3):239-42. DOI: 10.1016/j.neulet.2005.01.046. View

Aston-Jones G, Smith R, Moorman D, Richardson K . Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology. 2008; 56 Suppl 1:112-21. PMC: 2635332. DOI: 10.1016/j.neuropharm.2008.06.060. View

Gotter A, Webber A, Coleman P, Renger J, Winrow C . International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev. 2012; 64(3):389-420. DOI: 10.1124/pr.111.005546. View

Peyron C, Tighe D, van den Pol A, de Lecea L, Heller H, Sutcliffe J . Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998; 18(23):9996-10015. PMC: 6793310. View

Porter R, Chan W, Coulton S, Johns A, Hadley M, Widdowson K . 1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett. 2001; 11(14):1907-10. DOI: 10.1016/s0960-894x(01)00343-2. View

Thorn D, An X, Zhang Y, Pigini M, Li J . Characterization of the hypothermic effects of imidazoline I₂ receptor agonists in rats. Br J Pharmacol. 2012; 166(6):1936-45. PMC: 3402816. DOI: 10.1111/j.1476-5381.2012.01894.x. View

10.

Roecker A, Coleman P . Orexin receptor antagonists: medicinal chemistry and therapeutic potential. Curr Top Med Chem. 2008; 8(11):977-87. DOI: 10.2174/156802608784936746. View

11.

Scammell T, Winrow C . Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2010; 51:243-66. PMC: 3058259. DOI: 10.1146/annurev-pharmtox-010510-100528. View

12.

Harris D, Clayton T, Cook J, Sahbaie P, Halliwell R, Furtmuller R . Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the alpha5 subunit. J Med Chem. 2008; 51(13):3788-803. DOI: 10.1021/jm701433b. View

13.

Harris G, Wimmer M, Aston-Jones G . A role for lateral hypothalamic orexin neurons in reward seeking. Nature. 2005; 437(7058):556-9. DOI: 10.1038/nature04071. View

14.

Neubauer D . Almorexant, a dual orexin receptor antagonist for the treatment of insomnia. Curr Opin Investig Drugs. 2010; 11(1):101-10. View

15.

McElhinny Jr C, Lewin A, Mascarella S, Runyon S, Brieaddy L, Carroll F . Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies. Bioorg Med Chem Lett. 2012; 22(21):6661-4. DOI: 10.1016/j.bmcl.2012.08.109. View

16.

Kodadek T, Cai D . Chemistry and biology of orexin signaling. Mol Biosyst. 2010; 6(8):1366-75. PMC: 3379554. DOI: 10.1039/c003468a. View

17.

Hollander J, Lu Q, Cameron M, Kamenecka T, Kenny P . Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A. 2008; 105(49):19480-5. PMC: 2614786. DOI: 10.1073/pnas.0808023105. View

18.

Langmead C, Jerman J, Brough S, Scott C, Porter R, Herdon H . Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol. 2003; 141(2):340-6. PMC: 1574197. DOI: 10.1038/sj.bjp.0705610. View

19.

Sutcliffe J, De Lecea L . The hypocretins: setting the arousal threshold. Nat Rev Neurosci. 2002; 3(5):339-49. DOI: 10.1038/nrn808. View

20.

Boss C, Brisbare-Roch C, Jenck F . Biomedical application of orexin/hypocretin receptor ligands in neuroscience. J Med Chem. 2009; 52(4):891-903. DOI: 10.1021/jm801296d. View