4-Hydroxypiperidines and their flexible 3-(amino)propyloxy analogues as non-imidazole histamine H3 receptor antagonist
| Autor: | Daniel McNaught Flores, Wiesława Agnieszka Fogel, Rob Leurs, Krzysztof Walczyński, Beata Olszewska, Anna Stasiak |
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| Přispěvatelé: | AIMMS, Medicinal chemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine N-methyl-5-{[1-(ω-substitutedalkyl)piperidin-4-yl]oxy}-N-propylpentan-1-amines Guinea Pigs histamine H3 receptor non-imidazole antagonists Pharmacology Article Catalysis lcsh:Chemistry Inorganic Chemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines In vivo 5-{3-[ω-substitutedalkyl](methyl)aminopropoxy}-N-methyl-N-propylpentan-1-amines Ciproxifan medicine Animals Humans Receptors Histamine H3 Inverse agonist Rats Wistar Physical and Theoretical Chemistry Neurotransmitter lcsh:QH301-705.5 Molecular Biology Spectroscopy Amination Thioperamide Organic Chemistry Antagonist N-methyl-5-{[1-(ω-substitutedalkyl) piperidin-4-yl]oxy}-N-propylpentan-1-amines General Medicine Rats Computer Science Applications HEK293 Cells 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 chemistry Histamine H3 receptor Histamine H receptor non-imidazole antagonists 030217 neurology & neurosurgery Histamine Histamine H3 Antagonists medicine.drug |
| Zdroj: | International Journal of Molecular Sciences; Volume 19; Issue 4; Pages: 1243 International Journal of Molecular Sciences International Journal of Molecular Sciences, 19:1243, 1-19. Multidisciplinary Digital Publishing Institute (MDPI) Olszewska, B, Stasiak, A, McNaught Flores, D, Fogel, W A, Leurs, R & Walczyński, K 2018, ' 4-Hydroxypiperidines and their flexible 3-(amino)propyloxy analogues as non-imidazole histamine H 3 receptor antagonist : Further structure-activity relationship exploration and in vitro and in vivo pharmacological evaluation ', International Journal of Molecular Sciences, vol. 19, 1243, pp. 1-19 . https://doi.org/10.3390/ijms19041243 International Journal of Molecular Sciences, Vol 19, Iss 4, p 1243 (2018) |
| ISSN: | 1661-6596 |
| DOI: | 10.3390/ijms19041243 |
| Popis: | 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’ brain in a manner and degree similar to the reference H3 antagonist Ciproxifan. |
| Databáze: | OpenAIRE |
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