Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines
H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-02-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1420-3049/23/2/326 |
| _version_ | 1819241267984334848 |
|---|---|
| author | Roman Guryn Marek Staszewski Anna Stasiak Daniel McNaught Flores Wiesława Agnieszka Fogel Rob Leurs Krzysztof Walczyński |
| author_facet | Roman Guryn Marek Staszewski Anna Stasiak Daniel McNaught Flores Wiesława Agnieszka Fogel Rob Leurs Krzysztof Walczyński |
| author_sort | Roman Guryn |
| collection | DOAJ |
| description | H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS-531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior. |
| first_indexed | 2024-12-23T14:21:12Z |
| format | Article |
| id | doaj.art-480147e5a58a45b09f09361c187ad6e2 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-23T14:21:12Z |
| publishDate | 2018-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-480147e5a58a45b09f09361c187ad6e22022-12-21T17:43:47ZengMDPI AGMolecules1420-30492018-02-0123232610.3390/molecules23020326molecules23020326Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazinesRoman Guryn0Marek Staszewski1Anna Stasiak2Daniel McNaught Flores3Wiesława Agnieszka Fogel4Rob Leurs5Krzysztof Walczyński6Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszyńskiego 1, 90-145 Łódź, PolandDepartment of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszyńskiego 1, 90-145 Łódź, PolandDepartment of Hormone Biochemistry, Medical University of Lodz, ul. Żeligowskiego 7/9, 90-752 Łódź, PolandAmsterdam Institute of Molecules, Medicines & Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The NetherlandsDepartment of Hormone Biochemistry, Medical University of Lodz, ul. Żeligowskiego 7/9, 90-752 Łódź, PolandAmsterdam Institute of Molecules, Medicines & Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The NetherlandsDepartment of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszyńskiego 1, 90-145 Łódź, PolandH3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS-531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior.http://www.mdpi.com/1420-3049/23/2/326histamine H3 receptor non-imidazole antagonistsN-methyl-N-ω-phenylalkyl-ω-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]alkan-1-amines |
| spellingShingle | Roman Guryn Marek Staszewski Anna Stasiak Daniel McNaught Flores Wiesława Agnieszka Fogel Rob Leurs Krzysztof Walczyński Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines Molecules histamine H3 receptor non-imidazole antagonists N-methyl-N-ω-phenylalkyl-ω-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]alkan-1-amines |
| title | Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines |
| title_full | Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines |
| title_fullStr | Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines |
| title_full_unstemmed | Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines |
| title_short | Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines |
| title_sort | non imidazole histamine h3 ligands part vii synthesis in vitro and in vivo characterization of 5 substituted 2 thiazol 4 n propylpiperazines |
| topic | histamine H3 receptor non-imidazole antagonists N-methyl-N-ω-phenylalkyl-ω-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]alkan-1-amines |
| url | http://www.mdpi.com/1420-3049/23/2/326 |
| work_keys_str_mv | AT romanguryn nonimidazolehistamineh3ligandspartviisynthesisinvitroandinvivocharacterizationof5substituted2thiazol4npropylpiperazines AT marekstaszewski nonimidazolehistamineh3ligandspartviisynthesisinvitroandinvivocharacterizationof5substituted2thiazol4npropylpiperazines AT annastasiak nonimidazolehistamineh3ligandspartviisynthesisinvitroandinvivocharacterizationof5substituted2thiazol4npropylpiperazines AT danielmcnaughtflores nonimidazolehistamineh3ligandspartviisynthesisinvitroandinvivocharacterizationof5substituted2thiazol4npropylpiperazines AT wiesławaagnieszkafogel nonimidazolehistamineh3ligandspartviisynthesisinvitroandinvivocharacterizationof5substituted2thiazol4npropylpiperazines AT robleurs nonimidazolehistamineh3ligandspartviisynthesisinvitroandinvivocharacterizationof5substituted2thiazol4npropylpiperazines AT krzysztofwalczynski nonimidazolehistamineh3ligandspartviisynthesisinvitroandinvivocharacterizationof5substituted2thiazol4npropylpiperazines |