Dual Piperidine-Based Histamine H and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, and , differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σRs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (, , and ) for further biological evaluation. Compound showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.

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References

Stark H, Sippl W, Ligneau X, Arrang J, Ganellin C, Schwartz J . Different antagonist binding properties of human and rat histamine H3 receptors. Bioorg Med Chem Lett. 2001; 11(7):951-4. DOI: 10.1016/s0960-894x(01)00090-7. View

Ligneau X, Perrin D, Landais L, Camelin J, Calmels T, Berrebi-Bertrand I . BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology. J Pharmacol Exp Ther. 2006; 320(1):365-75. DOI: 10.1124/jpet.106.111039. View

Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang J . OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. J Chem Theory Comput. 2015; 12(1):281-96. DOI: 10.1021/acs.jctc.5b00864. View

Ruiz-Cantero M, Gonzalez-Cano R, Tejada M, Santos-Caballero M, Perazzoli G, Nieto F . Sigma-1 receptor: A drug target for the modulation of neuroimmune and neuroglial interactions during chronic pain. Pharmacol Res. 2020; 163:105339. DOI: 10.1016/j.phrs.2020.105339. View

Szczepanska K, Kincses A, Vincze K, Szymanska E, Latacz G, Kuder K . N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H receptor and cancer resistance proteins. Bioorg Med Chem Lett. 2020; 30(22):127522. DOI: 10.1016/j.bmcl.2020.127522. View

Lopes S, da Silva A, Rodrigues Arruda B, Morais T, Rios J, Trevisan M . Peripheral antinociceptive action of mangiferin in mouse models of experimental pain: role of endogenous opioids, K(ATP)-channels and adenosine. Pharmacol Biochem Behav. 2013; 110:19-26. DOI: 10.1016/j.pbb.2013.05.016. View

Hogendorf A, Hogendorf A, Popiolek-Barczyk K, Ciechanowska A, Mika J, Satala G . Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT receptor low-basicity agonists, potential neuropathic painkillers. Eur J Med Chem. 2019; 170:261-275. DOI: 10.1016/j.ejmech.2019.03.017. View

Godyn J, Zareba P, Lazewska D, Stary D, Reiner-Link D, Frank A . Cyanobiphenyls: Novel H receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease. Bioorg Chem. 2021; 114:105129. DOI: 10.1016/j.bioorg.2021.105129. View

Rai B, Tawa G, Katz A, Humblet C . Modeling G protein-coupled receptors for structure-based drug discovery using low-frequency normal modes for refinement of homology models: application to H3 antagonists. Proteins. 2009; 78(2):457-73. DOI: 10.1002/prot.22571. View

10.

Arena E, Dichiara M, Floresta G, Parenti C, Marrazzo A, Pittala V . Novel Sigma-1 receptor antagonists: from opioids to small molecules: what is new?. Future Med Chem. 2017; 10(2):231-256. DOI: 10.4155/fmc-2017-0164. View

11.

Schlegel B, Laggner C, Meier R, Langer T, Schnell D, Seifert R . Generation of a homology model of the human histamine H(3) receptor for ligand docking and pharmacophore-based screening. J Comput Aided Mol Des. 2007; 21(8):437-53. DOI: 10.1007/s10822-007-9127-x. View

12.

Axe F, Bembenek S, Szalma S . Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore. J Mol Graph Model. 2006; 24(6):456-64. DOI: 10.1016/j.jmgm.2005.10.005. View

13.

Tjolsen A, Berge O, Hunskaar S, Rosland J, Hole K . The formalin test: an evaluation of the method. Pain. 1992; 51(1):5-17. DOI: 10.1016/0304-3959(92)90003-T. View

14.

Imeri F, Stepanovska Tanturovska B, Zivkovic A, Enzmann G, Schwalm S, Pfeilschifter J . Novel compounds with dual S1P receptor agonist and histamine H receptor antagonist activities act protective in a mouse model of multiple sclerosis. Neuropharmacology. 2021; 186:108464. DOI: 10.1016/j.neuropharm.2021.108464. View

15.

Kim S, Fristrup P, Abrol R, Goddard 3rd W . Structure-based prediction of subtype selectivity of histamine H3 receptor selective antagonists in clinical trials. J Chem Inf Model. 2011; 51(12):3262-74. PMC: 3246544. DOI: 10.1021/ci200435b. View

16.

Salat K, Kolaczkowski M, Furgala A, Rojek A, Sniecikowska J, Varney M . Antinociceptive, antiallodynic and antihyperalgesic effects of the 5-HT receptor selective agonist, NLX-112 in mouse models of pain. Neuropharmacology. 2017; 125:181-188. DOI: 10.1016/j.neuropharm.2017.07.022. View

17.

Turnaturi R, Montenegro L, Marrazzo A, Parenti R, Pasquinucci L, Parenti C . Benzomorphan skeleton, a versatile scaffold for different targets: A comprehensive review. Eur J Med Chem. 2018; 155:492-502. DOI: 10.1016/j.ejmech.2018.06.017. View

18.

Chen X, Murawski A, Patel K, Crespi C, Balimane P . A novel design of artificial membrane for improving the PAMPA model. Pharm Res. 2008; 25(7):1511-20. DOI: 10.1007/s11095-007-9517-8. View

19.

Baumeister P, Erdmann D, Biselli S, Kagermeier N, Elz S, Bernhardt G . [(3) H]UR-DE257: development of a tritium-labeled squaramide-type selective histamine H2 receptor antagonist. ChemMedChem. 2014; 10(1):83-93. DOI: 10.1002/cmdc.201402344. View

20.

Mogilski S, Kubacka M, Lazewska D, Wiecek M, Gluch-Lutwin M, Tyszka-Czochara M . Aryl-1,3,5-triazine ligands of histamine H receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide. Inflamm Res. 2016; 66(1):79-95. PMC: 5209447. DOI: 10.1007/s00011-016-0997-z. View