Discovery of AD258 As a Sigma Receptor Ligand with Potent Antiallodynic Activity

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Aug 3

PMID 37535861

Authors

Maria Dichiara

Francesca Alessandra Ambrosio

Sang Min Lee

M Carmen Ruiz-Cantero

Jessica Lombino

Adriana Coricello

Giosue Costa

Dhara Shah

Giuliana Costanzo

Lorella Pasquinucci

Kyung No Son

Giuseppe Cosentino

Rafael Gonzalez-Cano

Agostino Marrazzo

Vinay Kumar Aakalu

Enrique J Cobos

Stefano Alcaro

Emanuele Amata

Affiliations

Soon will be listed here.

Abstract

The design and synthesis of a series of 2,7-diazaspiro[4.4]nonane derivatives as potent sigma receptor (SR) ligands, associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose characteristics. The most promising compounds were subjected to toxicity testing and subsequently screened for analgesic properties. Compound () exhibited negligible cellular toxicity and a high binding affinity to both SRs (S1R = 3.5 nM, S2R = 2.6 nM), but not for other pain-related targets, and exerted high potency in a model of capsaicin-induced allodynia, reaching the maximum antiallodynic effect at very low doses (0.6-1.25 mg/kg). Functional activity experiments showed that S1R antagonism is needed for the effects of and that it did not induce motor impairment. In addition, exhibited a favorable pharmacokinetic profile.

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References

Richmond W, Wogan M, Isbell J, Gordon W . Interstrain differences of in vitro metabolic stability and impact on early drug discovery. J Pharm Sci. 2010; 99(11):4463-8. DOI: 10.1002/jps.22179. View

Aydar E, Stratton D, Fraser S, Djamgoz M, Palmer C . Sigma-1 receptors modulate neonatal Na1.5 ion channels in breast cancer cell lines. Eur Biophys J. 2016; 45(7):671-683. DOI: 10.1007/s00249-016-1135-0. View

Moreno E, Moreno-Delgado D, Navarro G, Hoffmann H, Fuentes S, Rosell-Vilar S . Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects. J Neurosci. 2014; 34(10):3545-58. PMC: 3942573. DOI: 10.1523/JNEUROSCI.4147-13.2014. View

Amata E, Rescifina A, Prezzavento O, Arena E, Dichiara M, Pittala V . (+)-Methyl (1R,2S)-2-{[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate [(+)-MR200] Derivatives as Potent and Selective Sigma Receptor Ligands: Stereochemistry and Pharmacological Properties. J Med Chem. 2017; 61(1):372-384. DOI: 10.1021/acs.jmedchem.7b01584. View

Jia J, Cheng J, Wang C, Zhen X . Sigma-1 Receptor-Modulated Neuroinflammation in Neurological Diseases. Front Cell Neurosci. 2018; 12:314. PMC: 6158303. DOI: 10.3389/fncel.2018.00314. View

Turnaturi R, Chiechio S, Pasquinucci L, Spoto S, Costanzo G, Dichiara M . Novel -normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain. Molecules. 2022; 27(16). PMC: 9413390. DOI: 10.3390/molecules27165135. View

Diaz J, Garcia M, Torrens A, Caamano A, Enjo J, Sicre C . EST64454: a Highly Soluble σ Receptor Antagonist Clinical Candidate for Pain Management. J Med Chem. 2020; 63(23):14979-14988. DOI: 10.1021/acs.jmedchem.0c01575. View

Merlos M, Romero L, Zamanillo D, Plata-Salaman C, Vela J . Sigma-1 Receptor and Pain. Handb Exp Pharmacol. 2017; 244:131-161. DOI: 10.1007/164_2017_9. View

Aydar E, Palmer C, Klyachko V, Jackson M . The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron. 2002; 34(3):399-410. DOI: 10.1016/s0896-6273(02)00677-3. View

10.

Gaulton A, Bellis L, Bento A, Chambers J, Davies M, Hersey A . ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res. 2011; 40(Database issue):D1100-7. PMC: 3245175. DOI: 10.1093/nar/gkr777. View

11.

Sahn J, Mejia G, Ray P, Martin S, Price T . Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice. ACS Chem Neurosci. 2017; 8(8):1801-1811. PMC: 5715471. DOI: 10.1021/acschemneuro.7b00200. View

12.

Dichiara M, Artacho-Cordon A, Turnaturi R, Santos-Caballero M, Gonzalez-Cano R, Pasquinucci L . Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation. Eur J Med Chem. 2022; 230:114091. DOI: 10.1016/j.ejmech.2021.114091. View

13.

Lazkani A, Delespierre T, Bauduceau B, Pasquier F, Bertin P, Berrut G . Healthcare costs associated with elderly chronic pain patients in primary care. Eur J Clin Pharmacol. 2015; 71(8):939-47. DOI: 10.1007/s00228-015-1871-6. View

14.

Astashkina A, Mann B, Grainger D . A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol Ther. 2012; 134(1):82-106. DOI: 10.1016/j.pharmthera.2012.01.001. View

15.

Zampieri D, Fortuna S, Romano M, Amata E, Dichiara M, Marrazzo A . Design, synthesis and biological evaluation of novel aminopropylcarboxamide derivatives as sigma ligands. Bioorg Med Chem Lett. 2022; 72:128860. DOI: 10.1016/j.bmcl.2022.128860. View

16.

Gonzalez-Cano R, Montilla-Garcia A, Ruiz-Cantero M, Bravo-Caparros I, Tejada M, Nieto F . The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?. Neurosci Biobehav Rev. 2020; 113:238-261. DOI: 10.1016/j.neubiorev.2020.03.004. View

17.

Diaz J, Cuberes R, Berrocal J, Contijoch M, Christmann U, Fernandez A . Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862). J Med Chem. 2012; 55(19):8211-24. DOI: 10.1021/jm3007323. View

18.

Navarro G, Moreno E, Bonaventura J, Brugarolas M, Farre D, Aguinaga D . Cocaine inhibits dopamine D2 receptor signaling via sigma-1-D2 receptor heteromers. PLoS One. 2013; 8(4):e61245. PMC: 3630156. DOI: 10.1371/journal.pone.0061245. View

19.

Hiesinger K, Darin D, Proschak E, Krasavin M . Spirocyclic Scaffolds in Medicinal Chemistry. J Med Chem. 2020; 64(1):150-183. DOI: 10.1021/acs.jmedchem.0c01473. View

20.

Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W . Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013; 27(3):221-34. DOI: 10.1007/s10822-013-9644-8. View