{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:43:34Z","timestamp":1766486614455,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,4,19]],"date-time":"2018-04-19T00:00:00Z","timestamp":1524096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"departmental source of the Medical University of Lodz grant","award":["503\/3-016-01\/503-31-001","503\/5-087-02\/503-01"],"award-info":[{"award-number":["503\/3-016-01\/503-31-001","503\/5-087-02\/503-01"]}]},{"name":"COST Action","award":["CA 15135"],"award-info":[{"award-number":["CA 15135"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Presynaptic histamine H3 receptors (H3R) act as auto- or heteroreceptors controlling, respectively, the release of histamine and of other neurotransmitters in the central nervous system (CNS). The extracellular levels of several neurotransmitters are enhanced by H3R antagonists, and there is a great interest for potent, brain-penetrating H3 receptor antagonists\/inverse agonists to compensate for the neurotransmitter deficits present in various neurological disorders. We have shown that 1-[(benzylfuran-2-yl)methyl]piperidinyl-4-oxyl- and benzyl- derivatives of N-propylpentan-1-amines exhibit high in vitro potencies toward the guinea pig H3 receptor (jejunum), with pA2 = 8.47 and 7.79, respectively (the reference compound used was thioperamide with pA2 = 8.67). Furthermore, following the replacement of 4-hydroxypiperidine with a 3-(methylamino)propyloxy chain, the pA2 value for the first group decreased, whereas it increased for the second group. Here, we present data on the impact of elongating the aliphatic chain between the nitrogen of 4-hydroxypiperidine or 3-(methylamino)propan-1-ol and the lipophilic residue. Additionally, the most active compound in this series of non-imidazole H3 receptor antagonists\/inverse agonists, i.e., ADS-003, was evaluated for its affinity to the recombinant rat and human histamine H3 receptors transiently expressed in HEK-293T cells. It was shown that ADS-003, given parenterally for 5 days, reduced the food intake of rats, as well as changed histamine and noradrenaline concentrations in the rats\u2019 brain in a manner and degree similar to the reference H3 antagonist Ciproxifan.<\/jats:p>","DOI":"10.3390\/ijms19041243","type":"journal-article","created":{"date-parts":[[2018,4,20]],"date-time":"2018-04-20T04:24:21Z","timestamp":1524198261000},"page":"1243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["4-Hydroxypiperidines and Their Flexible 3-(Amino)propyloxy Analogues as Non-Imidazole Histamine H3 Receptor Antagonist: Further Structure\u2013Activity Relationship Exploration and In Vitro and In Vivo Pharmacological Evaluation"],"prefix":"10.3390","volume":"19","author":[{"given":"Beata","family":"Olszewska","sequence":"first","affiliation":[{"name":"Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszy\u0144skiego Street 1, 90-145 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Stasiak","sequence":"additional","affiliation":[{"name":"Department of Hormone Biochemistry, Medical University of Lodz, \u017beligowskiego Street 7\/9, 90-752 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"McNaught Flores","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecules, Medicines &amp; Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wies\u0142awa Agnieszka","family":"Fogel","sequence":"additional","affiliation":[{"name":"Department of Hormone Biochemistry, Medical University of Lodz, \u017beligowskiego Street 7\/9, 90-752 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Leurs","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecules, Medicines &amp; Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Walczy\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszy\u0144skiego Street 1, 90-145 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/302832a0","article-title":"Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor","volume":"302","author":"Arrang","year":"1983","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1471-4159.1988.tb04841.x","article-title":"H3 receptors control release of histamine in human brain","volume":"51","author":"Arrang","year":"1988","journal-title":"J. Neurochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1124\/mol.55.6.1101","article-title":"Cloning and functional expression of the human histamine H3 receptor","volume":"55","author":"Lovenberg","year":"1999","journal-title":"Mol. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1124\/mol.61.1.239","article-title":"Presynaptic H3 autoreceptors modulate histamine synthesis through cAMP pathway","volume":"61","author":"Ortiz","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/sj.bjp.0703194","article-title":"Histamine H3 receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves","volume":"129","author":"Blandizzi","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF01244933","article-title":"Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors","volume":"93","author":"Schlicker","year":"1993","journal-title":"Neural Transm. Gen. Sect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1007\/BF00182737","article-title":"Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex","volume":"337","author":"Schlicker","year":"1988","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1113\/jphysiol.2006.120493","article-title":"Histaminergic and glycinergic modulation of GABA release in the vestibular nuclei of normal and labyrinth ctomised rat","volume":"577","author":"Bergquist","year":"2006","journal-title":"J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.neuropharm.2006.08.001","article-title":"Pre-synaptic histamine H3 receptors regulate glutamate, but not GABA release in rat thalamus","volume":"52","author":"Gutierrez","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1111\/j.1476-5381.1996.tb16086.x","article-title":"Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats","volume":"119","author":"Blandina","year":"1996","journal-title":"Br. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Buccafusco, J.J. (2004). Cognitive enhancing effects of drugs that target histamine receptors. Cognition-Enhancing Drugs Milestones in Drug Therapy, Birkh\u00e4user Verlag.","DOI":"10.1007\/978-3-0348-7867-8"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/PL00005200","article-title":"Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice","volume":"357","author":"Onodera","year":"1998","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1007\/PL00000175","article-title":"Thioperamide, and cimetidine modulate acetylcholine release from the amygdala of freely moving rats","volume":"49","author":"Passani","year":"2000","journal-title":"Inflamm. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1111\/j.1476-5381.2012.02093.x","article-title":"Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: A systemic consideration of recent progress and perspectives","volume":"167","author":"Bhowmik","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7272","DOI":"10.1523\/JNEUROSCI.22-16-07272.2002","article-title":"Ciproxifan, a histamine H3-receptor antagonist\/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat","volume":"22","author":"Pillot","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1172\/JCI15784","article-title":"Targeted disruption of H3 receptors results in changes in brain histamine tone leading to an obese phenotype","volume":"110","author":"Takahashi","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0223-5234(00)00101-X","article-title":"Selective ligands as tools to study histamine receptors","volume":"35","author":"Timmerman","year":"2000","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"965","DOI":"10.2174\/1389557043403107","article-title":"Medicinal chemical and pharmacological aspects of imidazole-containing histamine H3 receptor antagonists","volume":"4","author":"Stark","year":"2004","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00210-002-0649-4","article-title":"Replacement of imidazole by a piperidine moiety differentially affects the potency of histamine H3-receptor antagonists","volume":"367","author":"Liedtke","year":"2003","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1159\/000063794","article-title":"Coordination of histamine H3 receptor antagonists with human adrenal cytochrome P450 enzymes","volume":"66","author":"Yang","year":"2002","journal-title":"Pharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1517\/13543784.2011.625010","article-title":"Several down, a few to go: Histamine H3 receptor ligands making the final push towards the market?","volume":"20","author":"Kuhne","year":"2011","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_22","unstructured":"Pomponi, S.A., Gullo, V.P., Horan, A.C., and Patel, M.G. (1994). Coval SUS (Harbor Branch Oceanographic Institution). (5352707), U.S. Patent."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.bmcl.2005.11.003","article-title":"Aplysamine-1 and related analogs as histamine H3 receptor antagonists","volume":"16","author":"Swanson","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1021\/jm030185v","article-title":"A new class of diamine-based human histamine H3 receptor antagonists: 4-(Aminoalkoxy)benzylamines","volume":"46","author":"Apodaca","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1124\/jpet.106.111039","article-title":"BF2.649 [1-{3-[3-(4 Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist\/antagonist at the human histamine H3 receptor","volume":"320","author":"Ligneau","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1021\/jm049212n","article-title":"4-phenoxypiperidines: Potent, conformationally restricted, non-imidazolehistamine H3 antagonists","volume":"48","author":"Dvorak","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_27","unstructured":"Cowart, M.D., Bennani, Y.L., Faghih, R., Gfesser, G.A., and Black, L.A. (2002). Abbott Laboratories, USA. (20020183309), U.S. Patent."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/ardp.201100428","article-title":"Synthesis and preliminary pharmacological investigation of new N-substituted-N-[\u03c9-(\u03c9-phenoxy-alkylpiperazin-1-yl)alkyl]guanidines as non-imidazole histamine H3 antagonists","volume":"345","author":"Staszewski","year":"2012","journal-title":"Arch. Pharm. Chem. Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1007\/s00044-012-0090-2","article-title":"1-Phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl]-piperazine derivatives as non-imidazole histamine H3-antagonists","volume":"22","author":"Staszewski","year":"2013","journal-title":"Med. Chem. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/ardp.200800070","article-title":"New 1-benzyl-4-hydroxypiperidine derivatives as non-imidazole histamine H3 receptor antagonists","volume":"341","author":"Figlus","year":"2008","journal-title":"Arch. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/cbdd.12206","article-title":"Structure-activity relationships of new 1-substitutedmethyl-4-[5-(N-methyl-N-propylamino)pentyloxy]piperidines and selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methy-l-N-propyl)-pentanediamines as H3-antagonists","volume":"83","year":"2014","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_32","first-page":"747","article-title":"A simple and rapid in vitro test system for the screening of histamine H3 ligands","volume":"105","author":"Vollinga","year":"1992","journal-title":"Methods Find. Exp. Clin. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.1016\/j.tetlet.2011.09.040","article-title":"Synthesis of new series of iboga analogues","volume":"52","author":"Sibasish","year":"2011","journal-title":"Tetrahedron Lett."},{"key":"ref_34","first-page":"48","article-title":"Some quantitative uses of drug antagonists","volume":"14","author":"Arunlakshana","year":"1959","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/j.1471-4159.2007.04752.x","article-title":"The Akt\/GSK-3b axis as a new signaling pathway of the histamine H3 receptor","volume":"103","author":"Bongers","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Guryn, R., Staszewski, M., Stasiak, A., McNaught Flores, D., Fogel, W.A., Leurs, R., and Walczy\u0144ski, K. (2018). Non-imidazole histamine H3 ligands. Part VII. Synthesis, in vitro and in vivo characterization of 5-substituted-2-thiazol-4-n-propylpiperazines. Molecules, 23.","DOI":"10.3390\/molecules23020326"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/j.1471-4159.1966.tb09873.x","article-title":"Regional studies of catecholamines in the rat Brain-I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various region of the brain","volume":"13","author":"Glowinski","year":"1966","journal-title":"J. Neurochem."},{"key":"ref_38","first-page":"288","article-title":"Histamine: Intraventricular injection suppresses ingestive behavior of the cat","volume":"206","author":"Clineschmidt","year":"1973","journal-title":"Arch. Int. Pharmacodyn. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.2337\/diabetes.53.9.2250","article-title":"Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity","volume":"53","author":"Masaki","year":"2004","journal-title":"Diabetes"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11527","DOI":"10.1073\/pnas.1322016111","article-title":"Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake","volume":"111","author":"Provensi","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.neuropharm.2015.07.002","article-title":"The histaminergic system as a target for the prevention of obesity and metabolic syndrome","volume":"106","author":"Provensi","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/S0022-3565(24)37840-1","article-title":"Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist","volume":"297","author":"Ligneau","year":"1998","journal-title":"JPET"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/j.1472-8206.1999.tb00330.x","article-title":"Histamine H3 receptor-mediated inhibition of noradrenaline release in the human brain","volume":"13","author":"Schlicker","year":"1999","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/s12031-015-0536-3","article-title":"Interaction between brain histamine and serotonin, norepinephrine, and dopamine systems: In vivo microdialysis and electrophysiology study","volume":"56","author":"Flik","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1111\/j.1471-4159.1972.tb01459.x","article-title":"Isotopic microassay of histamine, histidine, histidine decarboxylase and histamine methyltransferase in brain tissue","volume":"19","author":"Taylor","year":"1972","journal-title":"J. Neurochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/j.1471-4159.1982.tb08692.x","article-title":"Deamination of 5-hydroxytryptamine by both forms of monoamine oxidase in the rat brain","volume":"38","author":"Fowler","year":"1982","journal-title":"J. Neurochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/4\/1243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:01:20Z","timestamp":1760194880000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/4\/1243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,19]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,4]]}},"alternative-id":["ijms19041243"],"URL":"https:\/\/doi.org\/10.3390\/ijms19041243","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2018,4,19]]}}}