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Sains Malaysiana 51(10)(2022):
http://doi.org/10.17576/jsm-2022-5110-22
Antidepressant
Potential of Daidzein through Modulation of Endocannabinoid System by Targeting
Fatty Acid Amide Hydrolase
(Potensi Anti-kemurungan Daidzein melalui Modulasi Sistem Endokanabinoid dengan Menyasarkan Asid Lemak Amida Hidrolase)
WAHID
ZADA1, GHULAM MURTAZA2, GHAZALA IQBAL3,
GHULAM ABBAS4, SHUJAAT ALI KHAN1 & ABDUL MANNAN1,*
1Department of Pharmacy,
COMSATS University Islamabad, Abbottabad Campus 22060, Pakistan
2Department of Pharmacy,
COMSATS University Islamabad, Lahore Campus 5400, Pakistan
3Department of Pharmacy,
Kohat University of Science and Technology, Kohat, Pakistan
4Department of Pharmacology, Faculty of
Pharmacy Ziauddin University, Karachi Pakistan
Received:
17 March 2022/Accepted: 30 May 2022
Abstract
In
recent decades, the identification of natural compounds that modulate the
endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition has
provided an interesting area of research. Daidzein, which is an isoflavone, has
neurobiological activities that are effective against several neurological
disorders which include depression. This study aimed to investigate the FAAH inhibitory activity of Daidzein through in-silico analysis via
Molecular Operating Environment software together with the in-vitro FAAH
inhibitory assay. Furthermore, the anti-depressive effect of Daidzein (20
mg/kg) was examined via open field test and forced swim test in both male and
female mice groups. Finally, the level of depression and stress was measured by
the plasma corticosterone level. Molecular docking has shown the probable binding of Daidzein with the
FAAH enzyme via its ser-ser-lys catalytic triad.
Daidzein binds to the active pocket of FAAH with excellent binding energy of
-64.77 Kcal/mol and binding affinity of -11.77 Kcal/mol. The findings reported
that Daidzein inhibited the FAAH enzyme with IC50 value at 1.3±0.13
µM concentration. The open field test showed that Daidzein had no significant
effect on locomotory activity in both male and female groups compared to
fluoxetine and Arch-5HT group. Daidzein has significantly decreased the
immobility time in forced swim test, which is an indicator of an
anti-depressive effect. The corticosterone level that
regulates depression was significantly decreased in both male and female
Daidzein-treated mice groups. This study highlighted the role of Daidzein
as a therapeutic agent for depression via the inhibition of FAAH and modulation
of corticosterone levels.
Keywords: Corticosterone;
depression; endocannabinoid system; forced swim test; HPA-axis; molecular
docking; open field test
Abstrak
Dalam beberapa dekad kebelakangan ini, pengenalpastian sebatian semula jadi yang memodulasi sistem endokanabinoid oleh perencatan asid lemak amide hidrolase (FAAH) telah menyediakan bidang penyelidikan yang menarik.
Daidzein yang merupakan isoflavon, mempunyai aktiviti neurobiologi yang berkesan terhadap beberapa gangguan neurologi termasuk kemurungan. Penyelidikan ini bertujuan untuk mengkaji aktiviti perencatan FAAH Daidzein melalui analisis in-silico melalui perisian Persekitaran Kendalian Molekul bersama-sama dengan ujian perencatan FAAH in-vitro. Tambahan pula, kesan anti-kemurungan Daidzein (20 mg/kg) telah diperiksa melalui ujian lapangan terbuka dan ujian berenang paksa pada kumpulan tikus jantan dan betina. Akhirnya, tahap kemurungan dan tekanan diukur dengan tahap kortikosteron plasma. Dok molekul telah menunjukkan kemungkinan pengikatan Daidzein dengan enzim FAAH melalui triad pemangkin ser-ser-lys. Daidzein mengikat pada poket aktif FAAH dengan tenaga pengikat yang sangat baik iaitu -64.77 Kcal/mol dan pertalian mengikat -11.77 Kcal/mol. Hasil menunjukkan bahawa Daidzein merencat enzim FAAH dengan nilai IC50 pada kepekatan 1.3±0.13 µM. Ujian lapangan terbuka menunjukkan bahawa Daidzein tidak mempunyai kesan yang signifikan terhadap aktiviti lokomotor pada kedua-dua kumpulan jantan dan betina berbanding kumpulan fluoksetin dan Arch-5HT. Daidzein telah mengurangkan dengan ketara masa pergerakan dalam ujian berenang paksa yang merupakan penunjuk kesan anti-kemurungan. Tahap kortikosteron yang mengawal kemurungan telah menurun dengan ketara pada kumpulan tikus jantan dan betina yang dirawat Daidzein.
Kajian ini menekankan peranan Daidzein sebagai agen terapeutik untuk kemurungan melalui perencatan FAAH dan modulasi tahap kortikosteron.
Kata kunci: Dok molekul; kemurungan; kortikosteron; paksiHPA; sistem endokanabinoid; ujian berenang paksa; ujian lapangan terbuka
REFERENCES
Ahmad, H., Rauf, K., Zada, W.,
McCarthy, M., Abbas, G., Anwar, F. & Shah, A.J. 2020. Kaempferol
facilitated extinction learning in contextual fear conditioned rats via
inhibition of fatty-acid amide hydrolase. Molecules 25(20): 4683.
Alexopoulos, G.S. 2019. Mechanisms
and treatment of late-life depression. Translational
Psychiatry 9(1): 1-16.
Almukadi, H., Wu, H., Böhlke, M.,
Kelley, C.J., Maher, T.J. & Pino-Figueroa, A. 2013. The macamide
N-3-methoxybenzyl-linoleamide is a time-dependent fatty acid amide hydrolase
(FAAH) inhibitor. Molecular Neurobiology 48(2): 333-339.
Alshehri, M.M., Sharifi-Rad, J.,
Herrera-Bravo, J., Jara, E.L., Salazar, L.A., Kregiel, D., Uprety, Y., Akram,
M., Iqbal, M., Martorell, M., Torrens-Mas, M., Pons, D.G., Dastan, S.D.,
Cruz-Martins, N., Ozdemir, F.A., Kumar, M. & Cho, W.C. 2021. Therapeutic
potential of isoflavones with an emphasis on daidzein. Oxidative Medicine and Cellular Longevity 2021: 6331630.
Bari, M., Battista, N., Fezza, F.,
Gasperi, V. & Maccarrone, M. 2006. New insights into endocannabinoid
degradation and its therapeutic potential. Mini
Reviews in Medicinal Chemistry 6(3): 257-268.
Beck, A.T., Alford, B.A., Beck,
A.T. & Alford, B.A. 2014. Depression.
Philadelphia: University of Pennsylvania Press.
Bedse, G., Colangeli, R.,
Lavecchia, A.M., Romano, A., Altieri, F., Cifani, C., Cassano, T. &
Gaetani, S. 2014. Role of the basolateral amygdala in mediating the effects of
the fatty acid amide hydrolase inhibitor URB597 on HPA axis response to stress. European Neuropsychopharmacology 24(9): 1511-1523.
Borkotoky, S., Meena, C.K. &
Murali, A. 2016. Interaction analysis of T7 RNA polymerase with heparin and its
low molecular weight derivatives–an in silico approach. Bioinformatics and Biology Insights 10:
BBI. S40427.
Bruno, A., Lembo, F., Novellino,
E., Stornaiuolo, M. & Marinelli, L. 2014. Beyond radio-displacement
techniques for Identification of CB 1 Ligands: The First Application of a
Fluorescence-quenching Assay. Scientific
Reports 4(1): 1-9.
Can, A., Dao, D.T., Arad, M.,
Terrillion, C.E., Piantadosi, S.C. & Gould, T.D. 2012. The mouse forced
swim test. Journal of Visualized Experiments 59: e3638.
Castillo, P.E., Younts, T.J.,
Chávez, A.E. & Hashimotodani, Y. 2012. Endocannabinoid signaling and
synaptic function. Neuron 76(1):
70-81.
Chadwick, V.L., Rohleder, C.,
Koethe, D. & Leweke, F.M. 2020. Cannabinoids and the endocannabinoid system
in anxiety, depression, and dysregulation of emotion in humans. Current
Opinion in Psychiatry 33(1): 20-42.
Chen, L., Wang, X., Zhang, Y.,
Zhong, H., Wang, C., Gao, P. & Li, B. 2021. Daidzein alleviates
hypothalamic-pituitary-adrenal axis hyperactivity, ameliorates depression-like
behavior, and partly rectifies circulating cytokine imbalance in two rodent models
of depression. Frontiers in Behavioral Neuroscience 15: 671864.
Choi, R.C.Y., Zhu, J.T.T., Yung,
A.W.Y., Lee, P.S.C., Xu, S.L., Guo, A.J.Y., Zhu, K.Y., Dong, T.T.X. & Tsim,
K.W.K. 2013. Synergistic action of flavonoids, baicalein, and daidzein in
estrogenic and neuroprotective effects: A development of potential health
products and therapeutic drugs against Alzheimer’s disease. Evidence-Based Complementary and Alternative
Medicine 2013: 635694.
Cota, D., Steiner, M-A., Marsicano,
G., Cervino, C., Herman, J.P., Grubler, Y., Stalla, J., Pasquali, R., Lutz, B.
& Stalla, G.K. 2007. Requirement of cannabinoid receptor type 1 for the
basal modulation of hypothalamic-pituitary-adrenal axis function. Endocrinology 148(4): 1574-1581.
Cravatt, B.F., Giang, D.K., Mayfield,
S.P., Boger, D.L., Lerner, R.A. & Gilula, N.B. 1996. Molecular
characterization of an enzyme that degrades neuromodulatory fatty-acid
amides. Nature 384(6604): 83-87.
Cristino, L., Bisogno, T. & Di
Marzo, V. 2020. Cannabinoids and the expanded endocannabinoid system in
neurological disorders. Nature Reviews
Neurology 16(1): 9-29.
Cryan, J.F., Page, M.E. &
Lucki, I. 2005. Differential behavioral effects of the antidepressants
reboxetine, fluoxetine, and moclobemide in a modified forced swim test following
chronic treatment. Psychopharmacology 182(3): 335-344.
Fowler, C.J., Tiger, G.,
López-Rodríguez, M.L., Viso, A., Ortega-Gutiérrez, S. & Ramos, J.A. 2003.
Inhibition of fatty acid amidohydrolase, the enzyme responsible for the
metabolism of the endocannabinoid anandamide, by analogues of
arachidonoyl-serotonin. Journal of Enzyme
Inhibition and Medicinal Chemistry 18(3): 225-231.
Gaynes, B.N., Gavin, N.,
Meltzer-Brody, S., Lohr, K.N., Swinson, T., Gartlehner, G., Brody, S. &
Miller, W.C. 2005. Perinatal depression: Prevalence, screening accuracy, and
screening outcomes: Summary. AHRQ
Evidence Report Summaries.
Gould, T.D., Dao, D.T. &
Kovacsics, C.E. 2009. The open field test. Mood
and Anxiety Related Phenotypes in Mice. pp. 1-20.
Gu, Z-Y., An, S-C., Mao, Y. &
Zhang, Z-T. 2006. Study on the antidepressant effects of daidzein sulfonic
sodium [J]. Journal of Shaanxi Normal
University (Natural Science Edition) 3.
Guo, J.M., Xiao, B.X., Liu, D.H.,
Grant, M., Zhang, S., Lai, Y.F., Guo, Y.B. & Liu, Q. 2004. Biphasic effect
of daidzein on cell growth of human colon cancer cells. Food and Chemical Toxicology 42(10): 1641-1646.
Hintz, K.K. & Ren, J. 2004.
Phytoestrogenic isoflavones daidzein and genistein reduce
glucose‐toxicity‐induced cardiac contractile dysfunction in
ventricular myocytes. Endocrine Research 30(2): 215-223.
Jaiswal, S., Tripathi, R.K.P. &
Ayyannan, S.R. 2018. Scaffold hopping-guided design of some isatin based rigid
analogs as fatty acid amide hydrolase inhibitors: Synthesis and evaluation. Biomedicine and Pharmacotherapy 107:
1611-1623.
Johnson, D.S., Stiff, C.,
Lazerwith, S.E., Kesten, S.R., Fay, L.K., Morris, M., Beidler, D., Liimatta,
M.B., Smith, S.E. & Dudley. D.T. 2011. Discovery of PF-04457845: A highly
potent, orally bioavailable, and selective urea FAAH inhibitor. ACS Medicinal Chemistry Letters 2(2):
91-96.
Katona, I. & Freund, T.F. 2012.
Multiple functions of endocannabinoid signaling in the brain. Annual
Review of Neuroscience 35: 529-558.
Kessler, R.C. 2003. Epidemiology of
women and depression. Journal of
Affective Disorders 74(1): 5-13.
Khan, A., Musgnung, J., Ramey, T.,
Messig, M., Buckley, G. & Ninan, P.T. 2014. Abrupt discontinuation compared
with a 1-week taper regimen in depressed outpatients treated for 24 weeks with
desvenlafaxine 50 mg/d. Journal of
Clinical Psychopharmacology 34(3): 365-368.
Ko, Y-H., Kwon, S-H., Ma, S-X.,
Seo, J-Y., Lee, B-R., Kim, K., Kim, S.Y., Lee, S-Y. & Jang, C-G. 2018a. The
memory-enhancing effects of 7, 8, 4’-trihydroxyisoflavone, a major metabolite
of daidzein, are associated with activation of the cholinergic system and BDNF
signaling pathway in mice. Brain Research
Bulletin 142: 197-206.
Ko, Y-H., Kim, S.Y., Lee, S-Y.
& Jang, C-G. 2018b. 6, 7, 4′-Trihydroxyisoflavone, a major metabolite
of daidzein, improves learning and memory via the cholinergic system and the
p-CREB/BDNF signaling pathway in mice. European
Journal of Pharmacology 826: 140-147.
Kornstein, S.G., Schatzberg, A.F.,
Thase, M.E., Yonkers, K.A., McCullough, J.P., Keitner, G.I., Gelenberg, A.J.,
Ryan, C.E., Hess, A.L. & Harrison, W. 2000. Gender differences in chronic
major and double depression. Journal of
Affective Disorders 60(1): 1-11.
Krebs-Kraft, D.L., Hill, M.N.,
Hillard, C.J. & McCarthy, M.M. 2010. Sex difference in cell proliferation
in developing rat amygdala mediated by endocannabinoids has implications for
social behavior. Proceedings of the
National Academy of Sciences 107(47): 20535-20540.
Kuehner, C. 2003. Gender
differences in unipolar depression: An update of epidemiological findings and
possible explanations. Acta Psychiatrica
Scandinavica 108(3): 163-174.
Kumar, Y.N., Kumar, P.S., Sowjenya,
G., Rao, V.K., Yeswanth, S., Prasad, U.V., Pradeepkiran, J.A., Sarma, P.V.G.K.
& Bhaskar, M. 2012. Comparison and correlation of binding mode of ATP in
the kinase domains of Hexokinase family. Bioinformation 8(12): 543.
Lensink, M.F., Méndez, R. &
Wodak, S.J. 2007. Docking and scoring protein complexes: CAPRI 3rd edition. Proteins: Structure, Function, and
Bioinformatics 69(4): 704-718.
Lim, G.Y., Tam, W.W., Lu, Y., Ho,
C.S., Zhang, M.W. & Ho, R.C. 2018. Prevalence of depression in the
community from 30 countries between 1994 and 2014. Scientific Reports 8(1): 1-10.
McKinney, M.K. & Cravatt, B.F.
2005. Structure and function of fatty acid amide hydrolase. Annual
Review of Biochemistry 74: 411-432.
McKinney, M.K. & Cravatt, B.F.
2003. Evidence for distinct roles in catalysis for residues of the
serine-serine-lysine catalytic triad of fatty acid amide hydrolase. Journal of Biological Chemistry 278(39):
37393-37399.
Melo de Carvalho, I. 2015.
Neuropeptides in stress reactivity: Role of enkephalin in response to chronic
stress. PhD Dissertation. Bonn: Rheinische Friedrich Wilhems University (Unpublished).
Micale, V. & Drago, F. 2018.
Endocannabinoid system, stress and HPA axis. European Journal of Pharmacology 834: 230-239.
Micale, V., Tabiova, K., Kucerova,
J. & Drago, F. 2015. Role of the endocannabinoid system in depression: From
preclinical to clinical evidence. In Cannabinoid
Modulation of Emotion, Memory, and Motivation. New York: Springer. pp. 97-129.
Micale, V., Mazzola, C. &
Drago, F. 2007. Endocannabinoids and neurodegenerative diseases. Pharmacological
Research 56(5): 382-392.
Mileni, M., Kamtekar, S., Wood,
D.C., Benson, T.E., Cravatt, B.F. & Stevens, R.C. 2010. Crystal structure
of fatty acid amide hydrolase bound to the carbamate inhibitor URB597:
discovery of a deacylating water molecule and insight into enzyme inactivation. Journal of Molecular Biology 400(4):
743-754.
Mileni, M., Johnson, D.S., Wang,
Z., Everdeen, D.S., Liimatta, M., Pabst, B., Bhattacharya, K., Nugent, R.A.,
Kamtekar, S. & Cravatt, B.F. 2008. Structure-guided inhibitor design for
human FAAH by interspecies active site conversion. Proceedings of the National Academy of Sciences 105(35):
12820-12824.
Montanari, S., Scalvini, L.,
Bartolini, M., Belluti, F., Gobbi, S., Andrisano, V., Ligresti, A., Di Marzo,
V., Rivara, S. & Mor, M. 2016. Fatty acid amide hydrolase (FAAH), acetylcholinesterase
(AChE), and butyrylcholinesterase (BuChE): Networked targets for the
development of carbamates as potential anti-Alzheimer’s disease agents. Journal of Medicinal Chemistry 59(13):
6387-6406.
Morgese, M.G., Schiavone, S. &
Trabace, L. 2017. Emerging role of amyloid beta in stress response: Implication
for depression and diabetes. European
Journal of Pharmacology 817: 22-29.
Myllymäki, M.J., Käsnänen, H.,
Kataja, A.O., Lahtela-Kakkonen, M., Saario, S.M., Poso, A. & Koskinen,
A.M.P. 2009. Chiral 3-(4, 5-dihydrooxazol-2-yl) phenyl alkylcarbamates as novel
FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and
interaction fields. European Journal of
Medicinal Chemistry 44(10): 4179-4191.
Pan, M., Han, H., Zhong, C. &
Geng, Q. 2012. Effects of genistein and daidzein on hippocampus neuronal cell
proliferation and BDNF expression in H19-7 neural cell line. The Journal of Nutrition, Health & Aging 16(4): 389-394.
Parasuraman, S., Raveendran, R.
& Kesavan, R. 2010. Blood sample collection in small laboratory animals. Journal of Pharmacology &
Pharmacotherapeutics 1(2): 87.
Pflüger-Müller, B., Oo, J.A.,
Heering, J., Warwick, T., Proschak, E., Günther, S., Looso, M., Rezende, F.,
Fork, C. & Geisslinger, G. 2020. The endocannabinoid anandamide has an
anti-inflammatory effect on CCL2 expression in vascular smooth muscle cells. Basic Research in Cardiology 115(3):
1-16.
Prendergast, B.J., Onishi, K.G.
& Zucker, I. 2014. Female mice liberated for inclusion in neuroscience and
biomedical research. Neuroscience &
Biobehavioral Reviews 40: 1-5.
Ren, S-Y., Wang, Z-Z., Zhang, Y.
& Chen, N-H. 2020. Potential application of endocannabinoid system agents
in neuropsychiatric and neurodegenerative diseases - Focusing on FAAH/MAGL
inhibitors. Acta Pharmacologica Sinica 41(10): 1263-1271.
Ronis, M.J., Mercer, K.E., Shankar,
K., Pulliam, C., Pedersen, K., Ingelman-Sundberg, M., Friso, S., Samuelson, D.,
Del Valle, L. & Taylor, C. 2020. Potential role of gut microbiota, the
proto-oncogene PIKE (Agap2) and cytochrome P450 CYP2W1 in promotion of liver
cancer by alcoholic and nonalcoholic fatty liver disease and protection by
dietary soy protein. Chemico-Biological
Interactions 325: 109131.
Rosenzweig-Lipson, S., Beyer, C.E.,
Hughes, Z.A., Khawaja, X., Rajarao, S.J., Malberg, J.E., Rahman, Z., Ring, R.H.
& Schechter, L.E. 2007. Differentiating antidepressants of the future:
Efficacy and safety. Pharmacology &
Therapeutics 113(1): 134-153.
Schildkraut, J.J. 1965. The
catecholamine hypothesis of affective disorders: A review of supporting
evidence. American Journal of Psychiatry 122(5): 509-522.
Seillier, A., Aguilar, D.D. &
Giuffrida, A. 2014. The dual FAAH/MAGL inhibitor JZL195 has enhanced effects on
endocannabinoid transmission and motor behavior in rats as compared to those of
the MAGL inhibitor JZL184. Pharmacology
Biochemistry and Behavior 124: 153-159.
Śliwa, L. & Macura, B.
2005. Evaluation of cell membrane integrity of spermatozoa by hypoosmotic
swelling test–“water test” in mice after intraperitoneal Daidzein
administration. Archives of Andrology 51(6): 443-448.
Steiner, M.A. & Wotjak, C.T.
2008. Role of the endocannabinoid system in regulation of the
hypothalamic-pituitary-adrenocortical axis. Progress
in Brain Research 170: 397-432.
Sun, J-P. & Qian, K. 2011.
Effect of Daidzein on behavior and brain-derived neurotrophic factor of
hippocampus in rats with chronic stress depression. Herald of Medicine 4.
Thors, L., Burston, J.J., Alter,
B.J., McKinney, M.K., Cravatt, B.F., Ross, R.A., Pertwee, R.G., Gereau 4th,
R.W., Wiley, J.L. & Fowler, C.J. 2010. Biochanin A, a naturally occurring
inhibitor of fatty acid amide hydrolase. British
Journal of Pharmacology 160(3): 549-560.
Thors, L., Eriksson, J. &
Fowler, C.J. 2007. Inhibition of the cellular uptake of anandamide by genistein
and its analogue daidzein in cells with different levels of fatty acid amide
hydrolase‐driven uptake. British
Journal of Pharmacology 152(5): 744-750.
Toczek, M. & Malinowska, B.
2018. Enhanced endocannabinoid tone as a potential target of pharmacotherapy. Life Sciences 204: 20-45.
Uddin, Md. & Kabir, Md. 2019.
Emerging signal regulating potential of genistein against Alzheimer’s disease:
A promising molecule of interest. Frontiers
in Cell and Developmental Biology 7: 197.
Vázquez-Palacios, G.,
Bonilla-Jaime, H. & Velázquez-Moctezuma, J. 2005. Antidepressant effects of
nicotine and fluoxetine in an animal model of depression induced by neonatal
treatment with clomipramine. Progress in
Neuro-Psychopharmacology and Biological Psychiatry 29(1): 39-46.
Vinod, K.Y. & Hungund, B.L.
2006. Role of the endocannabinoid system in depression and suicide. Trends in Pharmacological Sciences 27(10): 539-545.
Wang, H., Xin, M.A., Bai, Y. &
Zhang, X. 2003. Relationship between vasodilatation effect of daidzein and
vascular endothelium. Chinese
Pharmacological Bulletin 8.
Wei, J., Yang, F., Gong, C., Shi,
X. & Wang, G. 2019. Protective effect of daidzein against
streptozotocin‐induced Alzheimer's disease via improving cognitive
dysfunction and oxidative stress in rat model. Journal of Biochemical and Molecular Toxicology 33(6): e22319.
Wilson, R.I. & Nicoll, R.A.
2002. Endocannabinoid signaling in the brain. Science 296(5568): 678-682.
Wu, Q., Wang, M., Chen, W., Wang,
K. & Wang, Y. 2021. Daidzein exerts neuroprotective activity against
MPTP‐induced Parkinson's disease in experimental mice and
lipopolysaccharide‐induced BV2 microglial cells. Journal of Biochemical and Molecular Toxicology 36(2): e22949.
Yin, A-Q., Wang, F. & Zhang, X.
2019. Integrating endocannabinoid signaling in the regulation of anxiety and
depression. Acta Pharmacologica Sinica 40(3): 336-341.
Zeng, S., Tai, F., Zhai, P., Yuan,
A., Jia, R. & Zhang, X. 2010. Effect of daidzein on anxiety, social
behavior and spatial learning in male Balb/cJ mice. Pharmacology Biochemistry and Behavior 96(1): 16-23.
Zhang, J., Hao, Q-Q., Liu, X.,
Jing, Z., Jia, W-Q., Wang, S-Q., Xu, W-R., Cheng, X-C. & Wang, R-L. 2017.
Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine
derivatives dually targeting AT1 and PPARγ. Oncotarget 8(15): 25612.
Zou, S. & Kumar, U. 2018.
Cannabinoid receptors and the endocannabinoid system: Signaling and function in
the central nervous system. International
Journal of Molecular Sciences 19(3): 833.
*Corresponding author; email:
abdulmannan_ka@yahoo.com
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