Peripheral 5-HT3A and DP2 targets as the basis for the analgesic action of the novel isoquinoline derivative G-104
D. A. Puzanov-Tyurin,
Yu. A. Fomina,
T. Y. Kalyuta,
A. A. Smoliak,
S. A. Astaf’eva,
E. N. Reshetova,
V. N. Strelnikov,
A. S. Fedonnikov https://doi.org/10.37489/2587-7836-2026-3-55-68
EDN: NVUXBI
Abstract
Relevance. The search for a potent and safe analgesic devoid of the disadvantages of opioids and non steroidal anti inflammatory drugs remains an unresolved challenge in pharmacology. The synthetic isoquinoline derivative 6 (3,3 dimethyl 3,4 dihydroisoquinolin 1 yl)aminohexanoic acid (G-104) has demonstrated marked analgesic activity in preclinical models; however, its molecular targets and mechanism of action have remained unidentified.
Objective. To predict the potential peripheral targets 5-HTЗА and DP2 and analgesic mechanism of this novel isoquinoline derivative using a comprehensive in silico analysis.
Methods. Target prediction (SwissTargetPrediction, SEA, TargetNet, PPB2), molecular docking (Glide), and molecular dynamics simulations (GROMACS) were performed.
Results. In combination with previously obtained experimental data, a hypothesis on the possible mechanism of G-104 analgesia is proposed. The serotonin 5-HT ЗА receptor and the prostaglandin DP₂ receptor were selected as potential targets. Docking revealed that G-104 forms complexes with both receptors characteristic of antagonists, and molecular dynamics for DP₂ confirmed the stability of the binding pose throughout the simulation trajectory. This dual peripheral mechanism—simultaneous inhibition of serotonergic pain modulation and pro inflammatory prostaglandin D₂ signaling—may be consistent with potent and prolonged analgesia observed in vivo and predicts a low risk of central and autonomic adverse effects.
Conclusion. The obtained results position G-104 as a potentially effective multitarget analgesic and pave the way for further preclinical investigations.
Keywords
6-(3,
3-dimethyl-3,
4-dihydroisoquinoline-1-yl)aminohexanoic acid,
analgesic activity,
pharmacodynamics,
molecular modeling,
prostaglandin receptor,
serotonin receptor
Supporting agencies: This work was performed as part of the implementation of the state assignment of the Ministry of Health of the Russian Federation "Development of a new non-opioid drug for the treatment of chronic pain syndromes in the elderly"; EGISU R&D No. 125061607031-8 dated 12.01.2026.
About the Authors
D. A. Puzanov-Tyurin
Saratov State Medical University named after V. I. Razumovsky
Russian Federation
Russian Federation
Daniil A. Puzanov-Tyurin — Postgraduate Student, Junior Research Fellow, Expert Chemist at the Laboratory for Research and Quality Control of Medicines
Saratov
Yu. A. Fomina
Saratov State Medical University named after V. I. Razumovsky
Russian Federation
Russian Federation
Yulia A. Fomina — PhD, Cand. Sci. (Chem.), Head of the Laboratory for Research and Quality Control of Medicines
Saratov
T. Y. Kalyuta
Saratov State Medical University named after V. I. Razumovsky
Russian Federation
Russian Federation
Tatyana Y. Kalyuta — PhD, Cand. Sci. (Med.), Associate Professor, Director of the Scientific and Educational Center for Clinical and Biomedical Research
Saratov
A. A. Smoliak
Institute of Technical Chemistry Ural Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
Andrey A. Smoliak — PhD, Cand. Sci. (Chem.), Senior Researcher at the Laboratory of active reagent synthesis
Perm
S. A. Astaf’eva
Institute of Technical Chemistry Ural Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
Svetlana A. Astaf’eva — PhD, Cand. Sci. (Engin.), Head of the Laboratory of Structural and Chemical Polymer Modification
Perm
E. N. Reshetova
Institute of Technical Chemistry Ural Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
Elena N. Reshetova — PhD, Cand. Sci. (Chem.), Senior Researcher at the Laboratory of active reagent synthesis
Perm
V. N. Strelnikov
Institute of Technical Chemistry Ural Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
Vladimir N. Strelnikov — Dr. Sci. (Engin.), Corresponding Member of the Russian Academy of Sciences, Director
Perm
A. S. Fedonnikov
Saratov State Medical University named after V. I. Razumovsky
Russian Federation
Russian Federation
Alexander S. Fedonnikov — Dr. Sci. (Med.), Associate Professor; Director of the Institute of Public Health and Humanitarian Problems of Medicine, Vice-Rector for Research
Saratov
References
1. Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16(5):821-47. doi: 10.18433/j3vw2f. PMID: 24393558.
2. Wang Y, Kong Q. A real-world data analysis of piroxicam in the FDA Adverse Event Reporting System (FAERS) database. Front Med (Lausanne). 2025 Oct 10;12:1687088. doi: 10.3389/fmed.2025.1687088.
3. Süleyman H, Demircan B, Karagöz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep. 2007 MayJun;59(3):247-58.
4. Vane JR, Botting RM. Mechanism of action of aspirin-like drugs. Semin Arthritis Rheum. 1997 Jun;26(6 Suppl 1):2-10. doi: 10.1016/s0049-0172(97)80046-7.
5. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008 Mar;11(2 Suppl):S105-20.
6. Cabedo N, Berenguer I, Figadère B, Cortes D. An overview on benzylisoquinoline derivatives with dopaminergic and serotonergic activities. Curr Med Chem. 2009;16(19):2441-67. doi: 10.2174/092986709788682100.
7. Shang XF, Yang CJ, Morris-Natschke SL, et al. Biologically active isoquinoline alkaloids covering 2014-2018. Med Res Rev. 2020 Nov;40(6):2212- 2289. doi: 10.1002/med.21703.
8. Mikhailovskii AG, Pogorelova ES, Chashchina SV, Pershina NN. Synthesis and analgesic activity of 3,3-dialkyl-substituted drotaverine analog. Khimiko-farmatsevticheskii zhurnal. 2021;55(1):19-24. (In Russ.). doi: 10.30906/0023-1134-2021-55-1-19-24.
9. Arifian H, Maharani R, Megantara S, et al. Amino-Acid-Conjugated Natural Compounds: Aims, Designs and Results. Molecules. 2022 Nov 7;27(21):7631. doi: 10.3390/molecules27217631.
10. Anikina LV, Vikharev YuB, Safin VA, et al. Antiinflammatory and analgesic activity of N-(3,3-dimethyl-3,4- dihydroisoquinolyl-1)-amino acids. Khimiko-farmatsevticheskii zhurnal. 2002;36(2):19-23. (In Russ.). EDN: SVVKRH.
11. Zenkova EA, Vdovina GP, Danilova VK, et al. A study of the analgesic activity and an assessment of the involvement of the opioid system in the implementation of the antinociceptive effect of the isoquinoline and hexanoic acid derivative compound G-104 in comparison with a narcotic analgesic (In Russ.). In: News of science: Proceedings of materials the international scientific conference; 2015 Aug 30 31; Karlovy Vary, Czech Republic; Moscow, Russia. Available from: https://books.eeescience.ru/downloads/news-of-science/. Ссылка активна на 07.07.2026. ISBN 978-5-00090-080-2
12. Zenkova EA. Preclinical study of compound G-104, a non-narcotic analgesic based on isoquinoline and hexanoic acid derivatives. [dissertation] Volgograd; 2017. (In Russ.). Доступно по: https://old.volgmed.ru/uploads/dsovet/thesis/2-792-zenkova_elena_andreevna.pdf Ссылка активна на 09.09.2026.
13. Ogarev NP Moscow State University. Razrabotka i validatsiya metodiki kolichestvennogo opredeleniya G-104 v biologicheskikh obraztsakh laboratornykh zhivotnykh: otchet o NIR: zaklyuchitel'nyy [Development and validation of a method for the quantitative determination of G-104 in biological samples of laboratory animals: research report: final. Moscow; 2025 Dec. Report No.: PK001/13/11/2025. (In Russ.).
14. Daina A, Zoete V. Testing the predictive power of reverse screening to infer drug targets, with the help of machine learning. Commun Chem. 2024 May 9;7(1):105. doi: 10.1038/s42004-024-01179-2.
15. Keiser MJ, Roth BL, Armbruster BN, et al. Relating protein pharmacology by ligand chemistry. Nat Biotechnol. 2007 Feb;25(2):197-206. doi: 10.1038/nbt1284.
16. Yao ZJ, Dong J, Che YJ, et al. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models. J Comput Aided Mol Des. 2016 May;30(5):413-24. doi: 10.1007/s10822-016-9915-2.
17. Awale M, Reymond JL. Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning. J Chem Inf Model. 2019 Jan 28;59(1):10-17. doi: 10.1021/acs.jcim.8b00524.
18. Jain A, Jain K, Bhardawaj N. Analgesic efficacy of low-dose intrathecal neostigmine in combination with fentanyl and bupivacaine for total knee replacement surgery. J Anaesthesiol Clin Pharmacol. 2012 Oct;28(4):486-90. doi: 10.4103/0970-9185.101927
19. Basnet A, Butler S, Honoré PH, et al. Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study. Acta Anaesthesiol Scand. 2014 Jan;58(1):61-73. doi: 10.1111/aas.12218.
20. Ariel N, Ordentlich A, Barak D, et al. The 'aromatic patch' of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors. Biochem J. 1998 Oct 1;335 (Pt 1)(Pt 1):95-102. doi: 10.1042/bj3350095.
21. Wojtunik-Kulesza KA, Targowska-Duda K, Klimek K, et al. Volatile terpenoids as potential drug leads in Alzheimer’s disease. Open Chem. 2017;15:332-343. doi:10.1515/chem-2017-0040.
22. Ordentlich A, Barak D, Kronman C, et al. Contribution of aromatic moieties of tyrosine 133 and of the anionic subsite tryptophan 86 to catalytic efficiency and allosteric modulation of acetylcholinesterase. J Biol Chem. 1995 Feb 3;270(5):2082-91. doi: 10.1074/jbc.270.5.2082.
23. Faerber L, Drechsler S, Ladenburger S, et al. The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation. Eur J Pharmacol. 2007 Mar 29;560(1):1-8. doi: 10.1016/j.ejphar.2007.01.028.
24. Liao C, Guo J, Rui J, et al. 5-HT3a receptor contributes to neuropathic pain by regulating central sensitization in a rat with brachial plexus avulsion. Physiol Behav. 2024 Apr 1;277:114503. doi: 10.1016/j.physbeh.2024.114503.
25. Kayser V, Elfassi IE, Aubel B, et al. Mechanical, thermal and formalininduced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. Pain. 2007 Aug;130(3):235-248. doi: 10.1016/j.pain.2006.11.015.
26. McCleane GJ, Suzuki R, Dickenson AH. Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A double-blinded, placebo-controlled cross-over study. Anesth Analg. 2003 Nov;97(5):1474-1478. doi: 10.1213/01.ANE.0000085640.69855.51.
27. Hazai E, Joshi P, Skoviak EC, et al. A comprehensive study on the 5-hydroxytryptamine(3A) receptor binding of agonists serotonin and m-chlorophenylbiguanidine. Bioorg Med Chem. 2009 Aug 15;17(16):5796- 805. doi: 10.1016/j.bmc.2009.07.022.
28. Spier AD, Lummis SC. The role of tryptophan residues in the 5-Hydroxytryptamine(3) receptor ligand binding domain. J Biol Chem. 2000 Feb 25;275(8):5620-5. doi: 10.1074/jbc.275.8.5620.
29. Vikharev BYu. Antiinflammatory and analgesic activities of 3,3-dialkyl-3,4-dihydroisoquinoline and phenethylamide derivatives. [[dissertation] Tomsk; 2005. Доступно по: https://rusneb.ru/catalog/000199_000009_002753536/ Ссылка активна на 09.09.2026.
30. Abdel-Halim MS, Hamberg M, Sjöquist B, Anggård E. Identification of prostaglandin D2 as a major prostaglandin in homogenates of rat brain. Prostaglandins. 1977 Oct;14(4):633-43. doi: 10.1016/0090-6980(77)90190-3.
31. Kanda H, Kobayashi K, Yamanaka H, Noguchi K. COX-1-dependent prostaglandin D2 in microglia contributes to neuropathic pain via DP2 receptor in spinal neurons. Glia. 2013 Jun;61(6):943-56. doi: 10.1002/glia.22487.
32. Hirai H, Tanaka K, Yoshie O, et al. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med. 2001 Jan 15;193(2):255-61. doi: 10.1084/jem.193.2.255.
33. MacLean Scott E, Solomon LA, Davidson C, et al. Activation of Th2 cells downregulates CRTh2 through an NFAT1 mediated mechanism. PLoS One. 2018 Jul 3;13(7):e0199156. doi: 10.1371/journal.pone.0199156.
34. Pettipher R, Hansel TT, Armer R. Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov. 2007 Apr;6(4):313-25. doi: 10.1038/nrd2266.
35. Sidharta PN, Diamant Z, Dingemanse J. Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects. Fundam Clin Pharmacol. 2014 Dec;28(6):690-9. doi: 10.1111/fcp.12079.
36. Wang L, Yao D, Deepak RNVK, et al. Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition. Mol Cell. 2018 Oct 4;72(1):48-59.e4. doi: 10.1016/j.molcel.2018.08.009.
37. Issahaku AR, Agoni C, Soremekun OS, et al. Same Target, Different Therapeutic Outcomes: The Case of CAY10471 and Fevipiprant on CRTh2 Receptor in Treatment of Allergic Rhinitis and Asthma. Comb Chem High Throughput Screen. 2019;22(8):521-533. doi: 10.2174/1386207322666190919113006.
38. Karshikoff B, Tadros MA, Mackey S, Zouikr I. Neuroimmune modulation of pain across the developmental spectrum. Curr Opin Behav Sci. 2019 Aug;28:85-92. doi: 10.1016/j.cobeha.2019.01.010.
39. Choi CH, Kim WM, Lee HG, et al. Roles of opioid receptor subtype in the spinal antinociception of selective cyclooxygenase 2 inhibitor. Korean J Pain. 2010 Dec;23(4):236-41. doi: 10.3344/kjp.2010.23.4.236.
40. Nishiyama T. Analgesic effects of intrathecally administered celecoxib, a cyclooxygenase-2 inhibitor, in the tail flick test and the formalin test in rats. Acta Anaesthesiol Scand. 2006 Feb;50(2):228-33. doi: 10.1111/j.1399-6576.2006.00921.x.
41. Meagher EA. Cardiovascular and renovascular implications of COX- 2 inhibition. Curr Pharm Des. 2004;10(6):603-11. doi: 10.2174/1381612043453153.
42. Wallace JL, Muscará MN. Selective cyclo-oxygenase-2 inhibitors: cardiovascular and gastrointestinal toxicity. Dig Liver Dis. 2001 Dec;33 Suppl 2:S21-8. doi: 10.1016/s1590-8658(01)80155-9.
Review
For citations:
Puzanov-Tyurin D.A., Fomina Yu.A., Kalyuta T.Y., Smoliak A.A., Astaf’eva S.A., Reshetova E.N., Strelnikov V.N., Fedonnikov A.S. Peripheral 5-HT3A and DP2 targets as the basis for the analgesic action of the novel isoquinoline derivative G-104. Pharmacokinetics and Pharmacodynamics. 2026;(3):55-68. (In Russ.) https://doi.org/10.37489/2587-7836-2026-3-55-68. EDN: NVUXBI
Views:
16
JATS XML
Email this article 