Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives

Malika Khaiitova 1 *
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1 Department of Pharmacology, Kazakh National Medical University named after S.D. Asfendiyarov, Almaty, Kazakhstan
* Corresponding Author
J CLIN MED KAZ, Volume 20, Issue 4, pp. 60-67. https://doi.org/10.23950/jcmk/13541
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ABSTRACT

Background: The unique ability of piperidine to combine with various molecular fragments makes it possible to use its chemical structure to create new drugs with potential pharmacological effects. However, preliminary studies are required to predict the activity of new compounds in order to determine the direction of further preclinical studies.
Aim: This study aims at determining the potential targets and spectrum of biological activity of new piperidine derivatives by the in silico method.
Material and methods: Prediction of the effects on targets and the spectrum of biological activity of three new piperidine derivatives synthesized at the Bekturov Institute of Chemical Sciences JSC was analyzed in this study. The chemical structures of these compounds were studied in silico using the web tool SwissTargetPrediction to identify the most likely protein targets. PASS (Prediction of Activity Spectra for Substances) online tool was used to predict the possible pharmacological activity of the studied compounds.
Results: New modified piperidine derivatives are able to affect different enzymes, receptors, transport systems, voltage-gated ion channels, thereby providing a wide range of biological activities applicable in various fields of medicine. These substances represent interest in the treatment of cancer, central nervous system diseases, as local anesthetic, antiarrhythmic and antimicrobial agents, and are promising for pharmacological activity demonstration in preclinical studies.
Conclusion: A comprehensive analysis of the above results leads to the conclusion that the compounds under study should be considered as potential substances for the design of new highly effective medicinal agents with a wide range of practical applications.
Keywords: piperidine derivatives, computer prediction, biological activity spectra, SwissTargetPrediction, PASS, in silico

CITATION

Khaiitova M. Computer‐aided evaluation of targets and biological activity spectra for new piperidine derivatives. J CLIN MED KAZ. 2023;20(4):60-7. https://doi.org/10.23950/jcmk/13541

REFERENCES

  • Goel P, Alam O, Naim MJ, Nawaz F, Iqbal M, Alam MI. Recent advancement of piperidine moiety in treatment of cancer- A review. Eur J Med Chem. 2018;5(157):480-502. https://doi.org/10.1016/j.ejmech.2018.08.017
  • Källström S, Leino R. Synthesis of pharmaceutically active compounds containing a disubstituted piperidine framework. Bioorg Med Chem. 2008;16(2):601-35. https://doi.org/10.1016/j.bmc.2007.10.018
  • Holtschulte C, Börgel F, Westphälinger S, Schepmann D, Civenni G, Laurini E, et al. Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ Receptor Ligands with Antiproliferative Properties. ChemMedChem. 2022;17(7):e202100735. https://doi.org/10.1002/cmdc.202100735
  • Gong-Qing Liu, Till Opatz. Recent Advances in the Synthesis of Piperidines: Functionalization of Preexisting Ring Systems. Adv Heterocycl Chem. 2018;125:107-234. https://doi.org/10.1016/bs.aihch.2017.10.001
  • Rathore A, Asati V, Kashaw SK, Agarwal S, Parwani D, Bhattacharya S, et al. The Recent Development of Piperazine and Piperidine Derivatives as Antipsychotic Agents. Mini Rev Med Chem. 2021;21(3):362-379. https://doi.org/10.2174/1389557520666200910092327
  • Frolov NA, Vereshchagin AN. Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications. Int J Mol Sci. 2023;24(3):2937. https://doi.org/10.3390/ijms24032937
  • Martins ML, Eckert J, Jacobsen H, Dos Santos ÉC, Ignazzi R, de Araujo DR, et al. Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations. Int J Pharm. 2017;524(1-2):397-406. https://doi.org/10.1016/j.ijpharm.2017.03.051
  • Vasilyuk A.A., Kozlovsky V.I. Promising directions for the application of piperidine derivatives as structural components of neurotropic drugs (available in Russian). Vestnik VGMU. 2021;20(2):8-17. https://doi.org/10.22263/2312-4156.2021.2.8
  • Eder J, Herrling PL. Trends in Modern Drug Discovery. Handb Exp Pharmacol. 2016;232:3-22. https://doi.org/10.1007/164_2015_20
  • Corominas-Faja B, Santangelo E, Cuyàs E, Micol V, Joven J, Ariza X, et al. Computer-aided discovery of biological activity spectra for anti-aging and anti-cancer olive oil oleuropeins. Aging (Albany NY). 2014;6(9):731-41. https://doi.org/10.18632/aging.100691
  • U.S. Department of Health and Human Services. The drug development process. Available at: https://www.fda.gov/ForPatients/Approvals/Drugs/default.htm.
  • Parvathaneni V, Kulkarni NS, Muth A, Gupta V. Drug repurposing: a promising tool to accelerate the drug discovery process. Drug Discov Today. 2019;24(10):2076-2085. https://doi.org/10.1016/j.drudis.2019.06.014
  • Fleming N. How artificial intelligence is changing drug discovery. Nature. 2018;557(7707):55-57. https://doi.org/10.1038/d41586-018-05267-x
  • Zhu H. Big Data and Artificial Intelligence Modeling for Drug Discovery. Annu Rev Pharmacol Toxicol. 2020;60:573-589. https://doi.org/10.1146/annurev-pharmtox-010919-023324
  • Kanza S, Frey JG. A new wave of innovation in Semantic web tools for drug discovery. Expert Opin Drug Discov. 2019;14(5):433-444. https://doi.org/10.1080/17460441.2019.1586880
  • Cherkasov A, Muratov EN, Fourches D, Varnek A, Baskin II, Cronin M, et al. QSAR modeling: where have you been? Where are you going to? J Med Chem. 2014;57(12):4977-5010. https://doi.org/10.1021/jm4004285
  • Chan HCS, Shan H, Dahoun T, Vogel H, Yuan S. Advancing Drug Discovery via Artificial Intelligence. Trends Pharmacol Sci. 2019;40(8):592-604. https://doi.org/10.1016/j.tips.2019.06.004
  • Swiss Institute of Bioinformatics. Several components of the SwissDrugDesign project. Available at: Molecular Modelling Group (molecular-modelling.ch)
  • Dairov AK, Romanova MA, Sejdahmetova RB, Al'magambetov AM, Shorin SS, Adekenov SM, et al. Biologicheskij skrining prirodnyh soedinenij i ih proizvodnyh s primeneniem PASS-prognozirovanija [in Russian]. Vestnik KarGU. Serija - Biologija. Medicina. Geografija. 2015;4(80):10-17.
  • Adekenov SM. Seskviterpenovye laktony rastenij Kazahstana. Stroenie, svojstva i primenenie c. Dis. d-ra him.nauk. In-t bioorganich. himii RAN:Moskva; 1992. Р.377–381.
  • Adamov GV, Sajbel' OL, Mizina PG. Prognozirovanie mehanizmov farmakologicheskogo dejstvija mnogokomponentnogo rastitel'nogo jekstrakta s pomoshh'ju veb-resursa PASS online na primere travy cikorija obyknovennogo [in Russian]. Voprosy biologicheskoj, medicinskoj i farmacevticheskoj himii. 2021;12(24):36-40. https://doi.org/10.29296/25877313-2021-12-05
  • Basanagouda M, Jadhav VB, Kulkarni MV, Rao RN. Computer Aided Prediction of Biological Activity Spectra: Study of Correlation between Predicted and Observed Activities for Coumarin-4-Acetic Acids. Indian J Pharm Sci. 2011;73(1):88-92. https://doi.org/10.4103/0250-474X.89764
  • Han J, Wan M, Ma Z, Hu C, Yi H. Prediction of Targets of Curculigoside A in Osteoporosis and Rheumatoid Arthritis Using Network Pharmacology and Experimental Verification. Drug Des Devel Ther. 2020;14:5235-5250. https://doi.org/10.2147/DDDT.S282112
  • Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;47(W1):357-364. https://doi.org/10.1093/nar/gkz382
  • Daina A, Zoete V. Application of the SwissDrugDesign Online Resources in Virtual Screening. Int J Mol Sci. 2019;20(18):4612. https://doi.org/10.3390/ijms20184612
  • Filimonov DA, Lagunin AA, Gloriozova TA et al. Prediction of the Biological Activity Spectra of Organic Compounds Using the Pass Online Web Resource. Chem Heterocycl Comp. 2014;50(3):444-457. https://doi.org/10.1007/s10593-014-1496-1
  • Filimonov DA, Druzhilovskij DS, Lagunin AA, Gloriozova TA, Rudik AV, Dmitriev V et al. Komp'juternoe prognozirovanie spektrov biologicheskoj aktivnosti himicheskih soedinenij: vozmozhnosti i ogranichenija [in Russian]. Biomedical Chemistry: Research and Methods. 2018; 1(1):e00004. https://doi.org/10.18097/BMCRM00004
  • Wooller SK, Benstead-Hume G, Chen X, Ali Y, Pearl FMG. Bioinformatics in translational drug discovery. Biosci Rep. 2017;37(4):BSR20160180. https://doi.org/10.1042/BSR20160180
  • Vamathevan J, Clark D, Czodrowski P, Dunham I, Ferran E, Lee G, et al. Applications of machine learning in drug discovery and development. Nat Rev Drug Discov. 2019;18(6):463-477. https://doi.org/10.1038/s41573-019-0024-5
  • Deng J, Yang Z, Ojima I, Samaras D, Wang F. Artificial intelligence in drug discovery: applications and techniques. Brief Bioinform. 2022;23(1):bbab430. https://doi.org/10.1093/bib/bbab430
  • Bao J, Hunt JA, Miao S, Rupprecht KM, Stelmach JE, Liu L, et al. p38 MAP kinase inhibitors: metabolically stabilized piperidine-substituted quinolinones and naphthyridinones. Bioorg Med Chem Lett. 2006;16(1):64-8. https://doi.org/10.1016/j.bmcl.2005.09.065
  • McHardy T, Caldwell JJ, Cheung KM, Hunter LJ, Taylor K, Rowlands M, et al. Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J Med Chem. 2010;53(5):2239-49. https://doi.org/10.1021/jm901788j
  • Mavunkel BJ, Perumattam JJ, Tan X, Luedtke GR, Lu Q, Lim D, et al. Piperidine-based heterocyclic oxalyl amides as potent p38 alpha MAP kinase inhibitors. Bioorg Med Chem Lett. 2010;20(3):1059-62. https://doi.org/10.1016/j.bmcl.2009.12.031
  • Mesaros EF, Angeles TS, Albom MS, Wagner JC, Aimone LD, Wan W, et al. Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase. Bioorg Med Chem Lett. 2015;25(5):1047-52. https://doi.org/10.1016/j.bmcl.2015.01.019
  • Zhu M, Zhou H, Ma L, Dong B, Zhou J, Zhang G, et al. Design and evaluation of novel piperidine HIV-1 protease inhibitors with potency against DRV-resistant variants. Eur J Med Chem. 2021;220:113450. https://doi.org/10.1016/j.ejmech.2021.113450
  • Saify ZS, Nisa M, Azhar KF, Azim MK, Rasheed H, Mushtaq N, et al. Characterisation of Plasmodium falciparum aspartic protease inhibition by piperidine derivatives. Nat Prod Res. 2011;25(20):1965-8. https://doi.org/10.1080/14786419.2010.541881
  • Galasiti Kankanamalage AC, Kim Y, Damalanka VC, Rathnayake AD, Fehr AR, Mehzabeen N, et al. Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element. Eur J Med Chem. 2018;150:334-346. https://doi.org/10.1016/j.ejmech.2018.03.004
  • Lamani M, Malamas MS, Farah SI, Shukla VG, Almeida MF, Weerts CM, et al. Piperidine and piperazine inhibitors of fatty acid amide hydrolase targeting excitotoxic pathology. Bioorg Med Chem. 2019;27(23):115096. https://doi.org/10.1016/j.bmc.2019.115096
  • Thalji RK, McAtee JJ, Belyanskaya S, Brandt M, Brown GD, Costell MH, et al. Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett. 2013;23(12):3584-8. https://doi.org/10.1016/j.bmcl.2013.04.019
  • Sandanayaka V, Mamat B, Bhagat N, Bedell L, Halldorsdottir G, Sigthorsdottir H, et al. Discovery of novel leukotriene A4 hydrolase inhibitors based on piperidine and piperazine scaffolds. Bioorg Med Chem Lett. 2010;20(9):2851-4. https://doi.org/10.1016/j.bmcl.2010.03.047
  • Patterson S, Jones DC, Shanks EJ, Frearson JA, Gilbert IH, Wyatt PG, et al. Synthesis and evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues as inhibitors of trypanothione reductase. ChemMedChem. 2009;4(8):1341-53. https://doi.org/10.1002/cmdc.200900098
  • Uto Y, Kiyotsuka Y, Ueno Y, Miyazawa Y, Kurata H, Ogata T, et al. Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine]. Bioorg Med Chem Lett. 2010;20(2):746-54. https://doi.org/10.1016/j.bmcl.2009.11.043
  • Di Matteo M, Ammazzalorso A, Andreoli F, Caffa I, De Filippis B, Fantacuzzi M, et al. Synthesis and biological characterization of 3-(imidazol-1-ylmethyl)piperidine sulfonamides as aromatase inhibitors. Bioorg Med Chem Lett. 2016;26(13):3192-3194. https://doi.org/10.1016/j.bmcl.2016.04.078
  • Ferro S, De Luca L, Germanò MP, Buemi MR, Ielo L, Certo G, et al. Chemical exploration of 4-(4-fluorobenzyl)piperidine fragment for the development of new tyrosinase inhibitors. Eur J Med Chem. 2017;125:992-1001. https://doi.org/10.1016/j.ejmech.2016.10.030
  • Bautista-Aguilera OM, Samadi A, Chioua M, Nikolic K, Filipic S, Agbaba D, et al. N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor. J Med Chem. 2014;57(24):10455-63. https://doi.org/10.1021/jm501501a
  • He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP. Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors. J Med Chem. 2005;48(25):7970-9. https://doi.org/10.1021/jm050694s
  • Giancola JB, Bonifazi A, Cao J, Ku T, Haraczy AJ, Lam J, et al. Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability. Eur J Med Chem. 2020;208:112674. https://doi.org/10.1016/j.ejmech.2020.112674
  • Yamamoto S, Shibata T, Abe K, Oda K, Aoki T, Kawakita Y, et al. Discovery of 3-Chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide as a Potent Glycine Transporter 1 Inhibitor. Chem Pharm Bull (Tokyo). 2016;64(9):1321-37. https://doi.org/10.1248/cpb.c16-00314
  • Nencetti S, Demontis GC, Mazzoni MR, Betti L, Banti I, Rossello A, et al. 3-[(Aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives: high-affinity ligands for the serotonin transporter. J Pharm Pharmacol. 2007;59(10):1439-45. https://doi.org/10.1211/jpp.59.10.0016
  • Hanson DC, Nguyen A, Mather RJ, Rauer H, Koch K, Burgess LE, et al. UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation. Br J Pharmacol. 1999;126(8):1707-16. https://doi.org/10.1038/sj.bjp.0702480
  • Yabuki Y, Matsuo K, Izumi H, Haga H, Yoshida T, Wakamori M, et al. Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer. Neuropharmacology. 2017;117:1-13. https://doi.org/10.1016/j.neuropharm.2017.01.011
  • Suzuki S, Kuroda T, Kimoto H, Domon Y, Kubota K, Kitano Y, et al. Discovery of (phenoxy-2-hydroxypropyl)piperidines as a novel class of voltage-gated sodium channel 1.7 inhibitors. Bioorg Med Chem Lett. 2015;25(22):5419-23. https://doi.org/10.1016/j.bmcl.2015.09.005
  • Ishikawa M, Furuuchi T, Yamauchi M, Yokoyama F, Kakui N, Sato Y. Synthesis and structure-activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor. Bioorg Med Chem. 2010;18(14):5441-8. https://doi.org/10.1016/j.bmc.2010.04.052
  • Carroll FI, Dolle RE. The discovery and development of the N-substituted trans-3,4-dimethyl-4-(3'-hydroxyphenyl)piperidine class of pure opioid receptor antagonists. ChemMedChem. 2014;9(8):1638-54. https://doi.org/10.1002/cmdc.201402142
  • Langmead CJ, Fry VA, Forbes IT, Branch CL, Christopoulos A, Wood MD, et al. Probing the molecular mechanism of interaction between 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine (AC-42) and the muscarinic M(1) receptor: direct pharmacological evidence that AC-42 is an allosteric agonist. Mol Pharmacol. 2006;69(1):236-46. https://doi.org/10.1124/mol.105.017814
  • Koshizawa T, Morimoto T, Watanabe G, Fukuda T, Yamasaki N, Hagita S, et al. Discovery of novel spiro[chromane-2,4'-piperidine] derivatives as potent and orally bioavailable G-protein-coupled receptor 119 agonists. Bioorg Med Chem Lett. 2018;28(19):3236-3241. https://doi.org/10.1016/j.bmcl.2018.08.010
  • Sakairi M, Kogami M, Torii M, Makino M, Kataoka D, Okamoto R, et al. Synthesis and pharmacological profile of a new selective G-protein-coupled receptor 119 agonist; 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one. Chem Pharm Bull (Tokyo). 2012;60(9):1093-5. https://doi.org/10.1248/cpb.c12-00484
  • Khaiitova M, Seitaliyeva A, Satbayeva E, Serdalieva D, Nurgozhin T. Experimental study of the pharmacological activity of new azaheterocycles derivatives: A literature review. J Clin Med Kaz. 2022;19(1):16-22. https://doi.org/10.23950/jcmk/11680
  • Goel P, Alam O, Naim MJ, Nawaz F, Iqbal M, Alam MI. Recent advancement of piperidine moiety in treatment of cancer- A review. Eur J Med Chem. 2018;157:480-502. https://doi.org/10.1016/j.ejmech.2018.08.017
  • Wang CZ, Johnson KM. The role of caspase-3 activation in phencyclidine-induced neuronal death in postnatal rats. Neuropsychopharmacology. 2007;32(5):1178-94. https://doi.org/10.1038/sj.npp.1301202
  • 58Barletta M, Reed R. Local Anesthetics: Pharmacology and Special Preparations. Vet Clin North Am Small Anim Pract. 2019;49(6):1109-1125. https://doi.org/10.1016/j.cvsm.2019.07.004
  • Tikhonov DB, Zhorov BS. Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants. J Gen Physiol. 2017;149(4):465-481. https://doi.org/10.1085/jgp.201611668
  • Scholz H. Classification and mechanism of action of antiarrhythmic drugs. Fundam Clin Pharmacol. 1994;8(5):385-90. https://doi.org/10.1111/j.1472-8206.1994.tb00817.x
  • Vignon J, Pinet V, Cerruti C, Kamenka JM, Chicheportiche R. [3H]N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine ([3H]BTCP): a new phencyclidine analog selective for the dopamine uptake complex. Eur J Pharmacol. 1988;148(3):427-36. https://doi.org/10.1016/0014-2999(88)90122-7
  • Zhang J, Zhang P, Liu X, Fang K, Lin G. Synthesis and biological evaluation of (R)-N-(diarylmethylthio/sulfinyl)ethyl/propyl-piperidine-3-carboxylic acid hydrochlorides as novel GABA uptake inhibitors. Bioorg Med Chem Lett. 2007;17(13):3769-73. https://doi.org/10.1016/j.bmcl.2007.04.010
  • Paudel S, Acharya S, Yoon G, Kim KM, Cheon SH. Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors. Bioorg Med Chem. 2017;25(7):2266-2276. https://doi.org/10.1016/j.bmc.2017.02.051
  • Przuntek H, Müller T. Clinical efficacy of budipine in Parkinson's disease. J Neural Transm Suppl. 1999;56:75-82. https://doi.org/10.1007/978-3-7091-6360-3_3
  • Mary YS, Varghese HT, Panicker CY, Girisha M, Sagar BK, Yathirajan HS, et al. Vibrational spectra, HOMO, LUMO, NBO, MEP analysis and molecular docking study of 2,2-diphenyl-4-(piperidin-1-yl)butanamide. Spectrochim Acta A Mol Biomol Spectrosc. 2015;150:543-56. https://doi.org/10.1016/j.saa.2015.05.090
  • Dileep KV, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, et al. Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors. Int J Biol Macromol. 2021;170:415-423. https://doi.org/10.1016/j.ijbiomac.2020.12.118
  • Yu X, Gu X, Zhao Y, Wang F, Sun W, Qi C, et al. Collective synthesis of aspulvinone and its analogues by vinylogous aldol condensation of substituted tetronic acids with aldehydes. RSC Adv. 2023;13(7):4859-4864. https://doi.org/10.1039/d2ra08133d
  • Xin-Xin Liang, Xing-Jie Zhang, Ying-Xin Zhao, Jian Feng, Jie-Chun Zeng, Qiang-Qiang Shi, et al. Aspulvins A–H, Aspulvinone Analogues with SARS-CoV-2 Mpro Inhibitory and Anti-inflammatory Activities from an Endophytic Cladosporium sp. J. Nat. Prod. 2022;85(4):878-887. https://doi.org/10.1021/acs.jnatprod.1c01003
  • Jimenez TP, Zhu Z, Court MH. Association of cytochrome P450 2D15 (CYP2D15) nonsynonymous polymorphisms and exon 3 deleted RNA splice variant with CYP2D15 protein content and enzyme function in dog liver microsomes. J Vet Pharmacol Ther. 2023;46(2):77-90. https://doi.org/10.1111/jvp.13113
  • Puskar NL, Xiu X, Lester HA, Dougherty DA. Two neuronal nicotinic acetylcholine receptors, alpha4beta4 and alpha7, show differential agonist binding modes. J Biol Chem. 2011;286(16):14618-27. https://doi.org/10.1074/jbc.M110.206565
  • Yu A, Frishman WH. Imidazoline receptor agonist drugs: a new approach to the treatment of systemic hypertension. J Clin Pharmacol. 1996;36(2):98-111. https://doi.org/10.1002/j.1552-4604.1996.tb04174.x