Imidazoles As Serotonin Receptor Modulators for Treatment of Depression: Structural Insights and Structure-Activity Relationship Studies

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2023 Sep 28

PMID 37765177

Authors

Kapil Kumar Goel

Somesh Thapliyal

Rajeev Kharb

Gaurav Joshi

Arvind Negi

Bhupinder Kumar

Affiliations

Soon will be listed here.

Abstract

Serotoninergic signaling is identified as a crucial player in psychiatric disorders (notably depression), presenting it as a significant therapeutic target for treating such conditions. Inhibitors of serotoninergic signaling (especially selective serotonin reuptake inhibitors (SSRI) or serotonin and norepinephrine reuptake inhibitors (SNRI)) are prominently selected as first-line therapy for the treatment of depression, which benefits via increasing low serotonin levels and norepinephrine by blocking serotonin/norepinephrine reuptake and thereby increasing activity. While developing newer heterocyclic scaffolds to target/modulate the serotonergic systems, imidazole-bearing pharmacophores have emerged. The imidazole-derived pharmacophore already demonstrated unique structural characteristics and an electron-rich environment, ultimately resulting in a diverse range of bioactivities. Therefore, the current manuscript discloses such a specific modification and structural activity relationship (SAR) of attempted derivatization in terms of the serotonergic efficacy of the resultant inhibitor. We also featured a landscape of imidazole-based development, focusing on SAR studies against the serotoninergic system to target depression. This study covers the recent advancements in synthetic methodologies for imidazole derivatives and the development of new molecules having antidepressant activity via modulating serotonergic systems, along with their SAR studies. The focus of the study is to provide structural insights into imidazole-based derivatives as serotonergic system modulators for the treatment of depression.

References

Lindemann L, Porter R, Scharf S, Kuennecke B, Bruns A, von Kienlin M . Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. J Pharmacol Exp Ther. 2015; 353(1):213-33. DOI: 10.1124/jpet.114.222463. View

Zmudzki P, Satala G, Chlon-Rzepa G, Bojarski A, Kazek G, Siwek A . Structure-5-HT/D Receptor Affinity Relationship in a New Group of 1-Arylpiperazynylalkyl Derivatives of 8-Dialkylamino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione. Arch Pharm (Weinheim). 2016; 349(10):774-784. DOI: 10.1002/ardp.201600162. View

Ulak G, Mutlu O, Akar F, Komsuoglu F, Tanyeri P, Erden B . Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats. Pharmacol Biochem Behav. 2008; 90(4):563-8. DOI: 10.1016/j.pbb.2008.04.016. View

Tzschentke T . Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol. 1999; 56(6):613-72. DOI: 10.1016/s0301-0082(98)00060-4. View

Sahu B, Bhatia R, Kaur D, Choudhary D, Rawat R, Sharma S . Design, synthesis and biological evaluation of oxadiazole clubbed piperazine derivatives as potential antidepressant agents. Bioorg Chem. 2023; 136:106544. DOI: 10.1016/j.bioorg.2023.106544. View

Zagorska A, Jurczyk S, Pawlowski M, Dybala M, Nowak G, Tatarczynska E . Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives. Eur J Med Chem. 2009; 44(11):4288-96. DOI: 10.1016/j.ejmech.2009.07.014. View

Wilson A, Meethal S, Bowen R, Atwood C . Leuprolide acetate: a drug of diverse clinical applications. Expert Opin Investig Drugs. 2007; 16(11):1851-63. DOI: 10.1517/13543784.16.11.1851. View

Zhou J, Reidy M, OReilly C, Jarikote D, Negi A, Samali A . Decorated macrocycles via ring-closing double-reductive amination. identification of an apoptosis inducer of leukemic cells that at least partially antagonizes a 5-HT2 receptor. Org Lett. 2015; 17(7):1672-5. DOI: 10.1021/acs.orglett.5b00404. View

Siwach A, Verma P . Synthesis and therapeutic potential of imidazole containing compounds. BMC Chem. 2021; 15(1):12. PMC: 7893931. DOI: 10.1186/s13065-020-00730-1. View

10.

Bromidge S, Arban R, Bertani B, Bison S, Borriello M, Cavanni P . Design and synthesis of novel tricyclic benzoxazines as potent 5-HT(1A/B/D) receptor antagonists leading to the discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045). J Med Chem. 2010; 53(15):5827-43. DOI: 10.1021/jm100482n. View

11.

Edinoff A, Akuly H, Hanna T, Ochoa C, Patti S, Ghaffar Y . Selective Serotonin Reuptake Inhibitors and Adverse Effects: A Narrative Review. Neurol Int. 2021; 13(3):387-401. PMC: 8395812. DOI: 10.3390/neurolint13030038. View

12.

Singh D, Singh P, Srivastava P, Kakkar D, Pathak M, Tiwari A . Development and challenges in the discovery of 5-HT and 5-HT receptor ligands. Bioorg Chem. 2022; 131:106254. DOI: 10.1016/j.bioorg.2022.106254. View

13.

Borgeat A, Fuchs-Buder T, Gachoud J, Suter P . Overnight sedation with midazolam or propofol in the ICU: effects on sleep quality, anxiety and depression. Intensive Care Med. 1996; 22(11):1186-90. DOI: 10.1007/BF01709334. View

14.

Castillo Ramos V, Reyes C, Garcia G, Quesada M, Barrero F, Rabago J . ZIF-8 and Its Magnetic Functionalization as Vehicle for the Transport and Release of Ciprofloxacin. Pharmaceutics. 2022; 14(11). PMC: 9693427. DOI: 10.3390/pharmaceutics14112546. View

15.

Parwani D, Bhattacharya S, Rathore A, Mallick C, Asati V, Agarwal S . Current Insights into the Chemistry and Antitubercular Potential of Benzimidazole and Imidazole Derivatives. Mini Rev Med Chem. 2020; 21(5):643-657. DOI: 10.2174/1389557520666201102094401. View

16.

Cohen N, Stewart M, Gavathiotis E, Tepper J, Bruekner S, Koss B . A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol. 2012; 19(9):1175-86. PMC: 3582387. DOI: 10.1016/j.chembiol.2012.07.018. View

17.

Li S, Tan Y, Zhang L, Zhou C . Comprehensive Insights into Medicinal Research on Imidazole-Based Supramolecular Complexes. Pharmaceutics. 2023; 15(5). PMC: 10222694. DOI: 10.3390/pharmaceutics15051348. View

18.

Andrei G, Andrei B, Roxana P . Imidazole Derivatives and their Antibacterial Activity - A Mini-Review. Mini Rev Med Chem. 2020; 21(11):1380-1392. DOI: 10.2174/1389557520999201209213648. View

19.

Czopek A, Partyka A, Bucki A, Pawlowski M, Kolaczkowski M, Siwek A . Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives. Molecules. 2020; 25(17). PMC: 7504677. DOI: 10.3390/molecules25173868. View

20.

Adeyemi O, Eseola A, Plass W, Kato K, Otuechere C, Awakan O . The anti-parasite action of imidazole derivatives likely involves oxidative stress but not HIF-1α signaling. Chem Biol Interact. 2021; 349:109676. DOI: 10.1016/j.cbi.2021.109676. View