Exploring 1-adamantanamine As an Alternative Amine Moiety for Metabolically Labile Azepane Ring in Newly Synthesized Benzo[]thiazol-2(3)one σ Receptor Ligands

Overview

Journal Med Chem Res

Publisher Springer

Specialty Chemistry

Date 2021 Feb 15

PMID 33584084

Citations 4

Authors

Sebastiano Intagliata

Hebaalla Agha

Theresa A Kopajtic

Jonathan L Katz

Shyam H Kamble

Abhisheak Sharma

Bonnie A Avery

Christopher R McCurdy

Affiliations

Soon will be listed here.

Abstract

In this work we report the structure-activity relationships, binding properties, and metabolic stability studies of a series of benzo[]thiazol-2(3)one as sigma receptors (σRs) ligands. Specifically, to improve the metabolic stability of the cyclic amine fragment of our lead compound (), the metabolically unstable azepane ring was replaced with a 1-adatamantamine moiety. Within the synthesized analogs, compound had low nanomolar affinity for the σR ( = 7.2 nM) and moderate preference (61-fold) over the σR. metabolic stability studies showed a slight improvement of the metabolic stability for -, even though an extensive metabolism in rat liver microsomes is being observed. Furthermore, metabolic soft spot identification of suggested that the -methyl group of the adamantyl moiety is a major site of metabolism.

Citing Articles

UPLC-MS/MS method for the quantification of MCI-77, a novel sigma-1 receptor ligand, and its application to pharmacokinetic studies.

Popa R, Kamble S, Kanumuri R, King T, Berthold E, Intagliata S J Chromatogr B Analyt Technol Biomed Life Sci. 2022; 1196:123187.

PMID: 35278810 PMC: 10019089. DOI: 10.1016/j.jchromb.2022.123187.

Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity.

Romeo G, Ciaffaglione V, Amata E, Dichiara M, Calabrese L, Vanella L Molecules. 2021; 26(13).

PMID: 34202711 PMC: 8270315. DOI: 10.3390/molecules26133860.

Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective.

Fallica A, Pittala V, Modica M, Salerno L, Romeo G, Marrazzo A J Med Chem. 2021; 64(12):7926-7962.

PMID: 34076441 PMC: 8279423. DOI: 10.1021/acs.jmedchem.0c02265.

Development of New Benzylpiperazine Derivatives as σ Receptor Ligands with Antinociceptive and Anti-Allodynic Effects.

Romeo G, Bonanno F, Wilson L, Arena E, Modica M, Pittala V ACS Chem Neurosci. 2021; 12(11):2003-2012.

PMID: 34019387 PMC: 8291485. DOI: 10.1021/acschemneuro.1c00106.

References

Shen B, Park J, Hjornevik T, Cipriano P, Yoon D, Gulaka P . Radiosynthesis and First-In-Human PET/MRI Evaluation with Clinical-Grade [F]FTC-146. Mol Imaging Biol. 2017; 19(5):779-786. DOI: 10.1007/s11307-017-1064-z. View

Martin W, EADES C, Thompson J, Huppler R, Gilbert P . The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976; 197(3):517-32. View

Cheng Z, Lan D, Wu P, Zhu Y, Dong Y, Ma L . Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptors. Exp Neurol. 2007; 210(1):128-36. DOI: 10.1016/j.expneurol.2007.10.004. View

Su T . Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther. 1982; 223(2):284-90. View

Walker J, Bowen W, Walker F, Matsumoto R, de Costa B, Rice K . Sigma receptors: biology and function. Pharmacol Rev. 1990; 42(4):355-402. View

Salerno L, Pittala V, Modica M, Siracusa M, Intagliata S, Cagnotto A . Structure-activity relationships and molecular modeling studies of novel arylpiperazinylalkyl 2-benzoxazolones and 2-benzothiazolones as 5-HT(7) and 5-HT(1A) receptor ligands. Eur J Med Chem. 2014; 85:716-26. DOI: 10.1016/j.ejmech.2014.08.023. View

Intagliata S, Alsharif W, Mesangeau C, Fazio N, Seminerio M, Xu Y . Benzimidazolone-based selective σ receptor ligands: Synthesis and pharmacological evaluation. Eur J Med Chem. 2019; 165:250-257. PMC: 6369001. DOI: 10.1016/j.ejmech.2019.01.019. View

Hjornevik T, Cipriano P, Shen B, Park J, Gulaka P, Holley D . Biodistribution and Radiation Dosimetry of F-FTC-146 in Humans. J Nucl Med. 2017; 58(12):2004-2009. PMC: 6944163. DOI: 10.2967/jnumed.117.192641. View

Vilner B, Bowen W . Modulation of cellular calcium by sigma-2 receptors: release from intracellular stores in human SK-N-SH neuroblastoma cells. J Pharmacol Exp Ther. 2000; 292(3):900-11. View

10.

Alon A, Schmidt H, Wood M, Sahn J, Martin S, Kruse A . Identification of the gene that codes for the σ receptor. Proc Natl Acad Sci U S A. 2017; 114(27):7160-7165. PMC: 5502638. DOI: 10.1073/pnas.1705154114. View

11.

Marrazzo A, Prezzavento O, Pappalardo M, Bousquet E, Iadanza M, Pike V . Synthesis of (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives as high affinity probes for sigma1 and sigma2 binding sites. Farmaco. 2002; 57(1):45-53. DOI: 10.1016/s0014-827x(01)01170-3. View

12.

Ucar H, Cacciaguerra S, Spampinato S, Van Derpoorten K, Isa M, Kanyonyo M . 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives: novel, potent and selective sigma1 receptor ligands. Eur J Pharmacol. 1997; 335(2-3):267-73. DOI: 10.1016/s0014-2999(97)01248-x. View

13.

Liu J, Obando D, Liao V, Lifa T, Codd R . The many faces of the adamantyl group in drug design. Eur J Med Chem. 2011; 46(6):1949-63. DOI: 10.1016/j.ejmech.2011.01.047. View

14.

Nicholson H, Alsharif W, Comeau A, Mesangeau C, Intagliata S, Mottinelli M . Divergent Cytotoxic and Metabolically Stimulative Functions of Sigma-2 Receptors: Structure-Activity Relationships of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[]oxazol-2(3)-one (SN79) Derivatives. J Pharmacol Exp Ther. 2018; 368(2):272-281. PMC: 6346378. DOI: 10.1124/jpet.118.253484. View

15.

Poupaert J, Carato P, Colacino E, Yous S . 2(3H)-benzoxazolone and bioisosters as "privileged scaffold" in the design of pharmacological probes. Curr Med Chem. 2005; 12(7):877-85. DOI: 10.2174/0929867053507388. View

16.

Shen B, Behera D, James M, Reyes S, Andrews L, Cipriano P . Visualizing Nerve Injury in a Neuropathic Pain Model with [F]FTC-146 PET/MRI. Theranostics. 2017; 7(11):2794-2805. PMC: 5562216. DOI: 10.7150/thno.19378. View

17.

Georgiadis M, Karoutzou O, Foscolos A, Papanastasiou I . Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity. Molecules. 2017; 22(9). PMC: 6151391. DOI: 10.3390/molecules22091408. View

18.

Mavlyutov T, Duellman T, Kim H, Epstein M, Leese C, Davletov B . Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody. Neuroscience. 2016; 331:148-57. PMC: 5047027. DOI: 10.1016/j.neuroscience.2016.06.030. View

19.

James M, Shen B, Zavaleta C, Nielsen C, Mesangeau C, Vuppala P . New positron emission tomography (PET) radioligand for imaging σ-1 receptors in living subjects. J Med Chem. 2012; 55(19):8272-8282. PMC: 4106900. DOI: 10.1021/jm300371c. View

20.

Quirion R, Bowen W, Itzhak Y, Junien J, Musacchio J, Rothman R . A proposal for the classification of sigma binding sites. Trends Pharmacol Sci. 1992; 13(3):85-6. DOI: 10.1016/0165-6147(92)90030-a. View