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Consequently, there is a continuous need to search for new, safer, and more effective antidepressant therapeutics. Previous studies have suggested a potential association of brain histaminergic\/serotoninergic signaling and antidepressant- and anxiolytic-like effects. Here, we evaluated the in vivo antidepressant- and anxiolytic-like effects of the newly developed multiple-active ligand ST-2300. ST-2300 was developed from 5-HT2A\/2C inverse agonist pimavanserin (PIM, ACP-103) and incorporates a histamine H3 receptor (H3R) antagonist pharmacophore. Despite its parent compound, ST-2300 showed only moderate serotonin 5-HT2A antagonist\/inverse agonist affinity (Ki value of 1302 nM), but excellent H3R affinity (Ki value of 14 nM). In vivo effects were examined using forced swim test (FST), tail suspension test (TST), and the open field test (OFT) in C57BL\/6 mice. Unlike PIM, ST-2300 significantly increased the anxiolytic-like effects in OFT without altering general motor activity. In FST and TST, ST-2300 was able to reduce immobility time similar to fluoxetine (FLX), a recognized antidepressant drug. Importantly, pretreatment with the CNS-penetrant H3R agonist (R)-\u03b1-methylhistamine reversed the antidepressant-like effects of ST-2300 in FST and TST, but failed to reverse the ST-2300-provided anxiolytic effects in OFT. Present findings reveal critical structural features that are useful in a rational multiple-pharmacological approach to target H3R\/5-HT2A\/5-HT2C.<\/jats:p>","DOI":"10.3390\/biom12050683","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T08:31:55Z","timestamp":1652171515000},"page":"683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Novel Pimavanserin Derivative ST-2300 with Histamine H3 Receptor Affinity Shows Reduced 5-HT2A Binding, but Maintains Antidepressant- and Anxiolytic-like Properties in Mice"],"prefix":"10.3390","volume":"12","author":[{"given":"Karthikkumar","family":"Venkatachalam","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sicheng","family":"Zhong","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universitaetsstr. 1, 40225 Dusseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2055-4935","authenticated-orcid":false,"given":"Mariam","family":"Dubiel","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universitaetsstr. 1, 40225 Dusseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grzegorz","family":"Sata\u0142a","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Acadamy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0320-1487","authenticated-orcid":false,"given":"Bassem","family":"Sadek","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3336-1710","authenticated-orcid":false,"given":"Holger","family":"Stark","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universitaetsstr. 1, 40225 Dusseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0166-4328(01)00219-4","article-title":"The mechanism of spontaneous firing in histamine neurons","volume":"124","author":"Stevens","year":"2001","journal-title":"Behav. Brain Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1472-8206.1994.tb00789.x","article-title":"Modulation of neurotransmitter releaseviahistamine H3 heteroreceptors","volume":"8","author":"Schlicker","year":"1994","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_3","first-page":"221","article-title":"Histamine H3-receptor signaling in the heart: Possible involvement of Gi\/Go proteins and N-type Ca++ channels","volume":"269","author":"Endou","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1164\/rccm.201907-1284OC","article-title":"Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial","volume":"201","author":"Dauvilliers","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1124\/jpet.112.194126","article-title":"Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H3 Receptor Antagonist","volume":"343","author":"Esbenshade","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6890","DOI":"10.1016\/j.bmcl.2013.09.090","article-title":"Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists","volume":"23","author":"Wilson","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0166-4328(01)00379-5","article-title":"Effects of histamine H3 receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup","volume":"131","author":"Fox","year":"2002","journal-title":"Behav. Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s00213-003-1431-0","article-title":"H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization","volume":"167","author":"Komater","year":"2003","journal-title":"Psychopharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.nlm.2010.10.008","article-title":"Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APPTg2576 mouse model of Alzheimer\u2019s disease","volume":"95","author":"Bardgett","year":"2011","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13077","DOI":"10.1038\/s41598-018-31385-7","article-title":"The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism","volume":"8","author":"Eissa","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108775","DOI":"10.1016\/j.cbi.2019.108775","article-title":"The dual-active histamine H3 receptor antagonist and acetylcholine esterase inhibitor E100 ameliorates stereotyped repetitive behavior and neuroinflammmation in sodium valproate induced autism in mice","volume":"312","author":"Eissa","year":"2019","journal-title":"Chem. Interact."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"111517","DOI":"10.1016\/j.biopha.2021.111517","article-title":"The histamine H3R and dopamine D2R\/D3R antagonist ST-713 ameliorates autism-like behavioral features in BTBR T+tf\/J mice by multiple actions","volume":"138","author":"Venkatachalam","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.neuropharm.2015.10.023","article-title":"Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats","volume":"106","author":"Sadek","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.2147\/DDDT.S116192","article-title":"Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats","volume":"10","author":"Sadek","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s002130050882","article-title":"Effects of histamine H3 receptor ligands in experimental models of anxiety and depression","volume":"142","author":"Morales","year":"1999","journal-title":"Psychopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"627","DOI":"10.2147\/DDDT.S63088","article-title":"Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H3 receptor antagonist ST-1283","volume":"8","author":"Sadek","year":"2014","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6269","DOI":"10.1016\/j.bmcl.2013.09.081","article-title":"Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3\u2032S)-2-methyl-[1,3\u2032]bipyrrolidinyl-1\u2032-yl)phenyl] amide as histamine H3 receptor antagonist for the treatment of depression","volume":"23","author":"Gao","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/j.1476-5381.2009.00149.x","article-title":"Altered histamine H3 receptor radioligand binding in post-mortem brain samples from subjects with psychiatric diseases","volume":"157","author":"Jin","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1124\/jpet.105.097006","article-title":"Pharmacological and Behavioral Profile of N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N\u2032-(4-(2-methylpropyloxy)phenylmethyl) Carbamide (2R,3R)-Dihydroxybutanedioate (2:1) (ACP-103), a Novel 5-Hydroxytryptamine2A Receptor Inverse Agonist","volume":"317","author":"Vanover","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1474-4422(18)30039-5","article-title":"Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer\u2019s disease psychosis: A phase 2, randomised, placebo-controlled, double-blind study","volume":"17","author":"Ballard","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19m12928","DOI":"10.4088\/JCP.19m12928","article-title":"A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients with Major Depressive Disorder and an Inadequate Response to Therapy (CLARITY)","volume":"80","author":"Fava","year":"2019","journal-title":"J. Clin. Psychiatry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20m13425","DOI":"10.4088\/JCP.20m13425","article-title":"Effect of Adjunctive Pimavanserin on Sleep\/Wakefulness in Patients with Major Depressive Disorder","volume":"82","author":"Jha","year":"2020","journal-title":"J. Clin. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/ajmg.10099","article-title":"The 5-HT2Areceptor gene 102T\/C polymorphism is associated with suicidal behavior in depressed patients","volume":"105","author":"Arias","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/S0893-133X(00)00223-2","article-title":"RNA Editing of the Human Serotonin 5-HT2C Receptor Alterations in Suicide and Implications for Serotonergic Pharmacotherapy","volume":"24","author":"Niswender","year":"2001","journal-title":"Neuropsychopharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.jad.2020.08.051","article-title":"Effect of adjunctive pimavanserin on suicidal ideation in patients with major depression: Analysis of the CLARITY study","volume":"277","author":"Shelton","year":"2020","journal-title":"J. Affect. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1016\/j.bmc.2006.01.013","article-title":"Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 receptor antagonists","volume":"14","author":"Ligneau","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/sj.bjp.0705964","article-title":"Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist","volume":"143","author":"Barbier","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"126612","DOI":"10.1016\/j.bmcl.2019.08.016","article-title":"Rasagiline derivatives combined with histamine H3 receptor properties","volume":"29","author":"Lutsenko","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.bmcl.2008.09.012","article-title":"Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics","volume":"19","author":"Kottke","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1016\/S1359-6446(05)03625-1","article-title":"Keynote review: Histamine H3 receptor antagonists reach out for the clinic","volume":"10","author":"Celanire","year":"2005","journal-title":"Drug Discov. Today"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.ejmech.2018.02.015","article-title":"Novel indanone derivatives as MAO B\/H3R dual-targeting ligands for treatment of Parkinson\u2019s disease","volume":"148","author":"Affini","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","unstructured":"Thygesen, M., Schlienger, N., Tolf, B.-R., Blatter, F., and Berghausen, J. (2006). Salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N\u2032-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation. (WO2006036874A1)."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1021\/ol100419y","article-title":"First Metal-Containing Histamine H3 Receptor Ligands","volume":"12","author":"Sander","year":"2010","journal-title":"Org. Lett."},{"key":"ref_34","first-page":"97","article-title":"Search for Histamine H3 Receptor Antagonists with Combined Inhibitory Potency at N\u03c4-Methyltransferase: Ether Derivatives","volume":"60","author":"Apelt","year":"2005","journal-title":"Pharmazie"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1248\/cpb.58.1353","article-title":"Kojic Acid Derivatives as Histamine H3 Receptor Ligands","volume":"58","author":"Sander","year":"2010","journal-title":"Chem. Pharm. Bull."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ejphar.2010.12.033","article-title":"Receptor-specific functional efficacies of alkyl imidazoles as dual histamine H3\/H4 receptor ligands","volume":"654","author":"Kottke","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","first-page":"1247","article-title":"Distinct pharmacology of rat and human histamine H3 receptors: Role of two amino acids in the third transmembrane domain","volume":"131","author":"Ligneau","year":"2000","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction","volume":"22","author":"Cheng","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","first-page":"1071","article-title":"Regulation of the human histamine H1 receptor stably expressed in Chinese hamster ovary cells","volume":"117","author":"Smit","year":"1996","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1021\/bi802050d","article-title":"High Constitutive Activity and a G-Protein-Independent High-Affinity State of the Human Histamine H4-Receptor","volume":"48","author":"Schneider","year":"2009","journal-title":"Biochemistry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7186","DOI":"10.1016\/j.bmc.2009.08.059","article-title":"2,4-Diaminopyrimidines as histamine H4 receptor ligands\u2014Scaffold optimization and pharmacological characterization","volume":"17","author":"Sander","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.ejmech.2014.06.032","article-title":"Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands","volume":"83","author":"Ner","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12765","DOI":"10.1002\/anie.201706072","article-title":"Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases","volume":"56","author":"Hagenow","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.euroneuro.2012.01.008","article-title":"Hippocampus-specific deletion of tissue plasminogen activator \u201ctPA\u201d in adult mice impairs depression- and anxiety-like behaviors","volume":"22","author":"Bahi","year":"2012","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_45","first-page":"327","article-title":"Behavioral despair in mice: A primary screening test for antidepressants","volume":"229","author":"Porsolt","year":"1977","journal-title":"Arch. Int. Pharmacodyn. Ther."},{"key":"ref_46","first-page":"e3769","article-title":"The Tail Suspension Test","volume":"59","author":"Can","year":"2012","journal-title":"J. Vis. Exp."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Eissa, N., Azimullah, S., Jayaprakash, P., Jayaraj, R.L., Reiner, D., Ojha, S.K., Beiram, R., Stark, H., \u0141a\u017cewska, D., and Kie\u0107-Kononowicz, K. (2020). The Dual-Active Histamine H3 Receptor Antagonist and Acetylcholine Esterase Inhibitor E100 Alleviates Autistic-like Behaviors and Oxidative Stress in Valproic Acid Induced Autism in Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113996"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Eissa, N., Jayaprakash, P., Stark, H., \u0141a\u017cewska, D., Kie\u0107-Kononowicz, K., and Sadek, B. (2020). Simultaneous Blockade of Histamine H3 Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-like Behaviors in BTBR T+ tf\/J Mouse Model of Autism. Biomolecules, 10.","DOI":"10.3390\/biom10091251"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1007\/s11064-014-1293-3","article-title":"On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson\u2019s Psychosis","volume":"39","author":"Hacksell","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s40120-018-0095-y","article-title":"5HT6 Antagonists in the Treatment of Alzheimer\u2019s Dementia: Current Progress","volume":"7","author":"Andrews","year":"2018","journal-title":"Neurol. Ther."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/5\/683\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:08:44Z","timestamp":1760137724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/5\/683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,10]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["biom12050683"],"URL":"https:\/\/doi.org\/10.3390\/biom12050683","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,10]]}}}