It is known that pharmacophoric arylpiperazine fragment is well recognized by
5-HT_1A, 5-HT_2A, as well as 5-HT₇ receptors. Although the terminal amide fragment significantly affects binding of 1-arylpiperazine derivatives with serotonin receptors, its role is not clear yet. In our earlier attempt to find new 5-HT_1A/5-HT_2A receptor ligands several series of arylpiperazinylalkyl theophylline derivatives have been synthesized and their affinities for 5-HT_1A and 5-HT_2A were determined [1-3]. The selected compounds were potent 5-HT_1A receptor ligands [2]. In order to explain the influence of theophylline (purine-2,6-dione) moiety on serotonin receptors affinity, purine-2,6,8-trione analogues were obtained. Additionally the arylpiperazine fragment was modified by introduction of 1,2,3,4-tetrahydroisoquinoline.

Previously obtained 1,3-dimethyl-7-(3-chloroalkyl)-8-methoxy-purine-2,6-dione in the reaction with appropriate piperazine derivatives and 1,2,3,4-tetrahydroisoquinoline yielded final products, which were isolated as a hydrochloride salts. The purity of the compounds were controlled by TLC, the structures were confirmed by spectral (¹H-NMR, MS, UV), and C, H, N analyses.

The 7-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-7,9-dihydro-3H-purine-2,6,8-trione was preliminary evaluated for its affinity to 5-HT_1A, 5-HT_2A and 5-HT₇ receptors. It was found that this compound was 5-HT_2A receptor ligand (K_i = 63 nM) with moderate 5-HT_1A (K_i = 263 nM), and low 5-HT₇ (K_i = 1820 nM) receptor affinity.

References:

1. M. Pawłowski, G. Chłoń, et al.: Il Farmaco, 55, 461, 2000.

2. G. Chłoń, M. Pawłowski, et al.: Pol. J. Pharmacol., 53, 359, 2001.

3. P. Zajdel, A.J. Bojarski, H. Byrtus, G. Chłoń-Rzepa, et al.: Biomed. Chromatogr. 17, 312, 2003.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/6463 must be provided.

1. Serotonin transporter inhibitors inducing hypothermia at mice
2. Rational design and synthesis of new 5-HT₆R ligands with the use of bioisosteric strategies. Crystal structures, biological evaluation and molecular modeling studies.
3. Ligand-directed receptor trafficking
4. The highly versatile handle for synthesis of secondary amine derivatives with potential CNS activity: The Pipecolic Linker
5. Synthesis, anticonvulsant activity and 5-HT_1A/5-HT₇ receptors affinity of new 1-[(4-substituted-  piperazin-1-yl)-alkyl]- 3-methyl- 3-(2-methylpropyl)-pyrrolidine- 2,5-diones
6. The multiobjective based design, synthesis and evaluation of the arylsulfonamide/amide derivatives of arylxyethyl- and arylthioethyl- piperidines and pyrrolidines as a novel class of potent 5-HT₇ receptor antagonists
7. Tricyclic derivatives of theophylline as potential ligands of CNS
8. Homology modeling of G-protein coupled receptors
9. Induced Fit Homology Model of the 5-HT₆ Serotonin Receptor - Application for Virtual Screening
10. Identification of Novel 5-HT₇R Ligands via Multistep Virtual Screening of Commercially Available Compounds Databases
11. Examination of 5-HT₆ receptor affinity in the group of arylsulfonamide derivatives
12. Interaction fingerprints patterns. Binding mode analysis of mGlu2 receptor model based on docking studies
13. A novel handle for chemistry on solid support: the Pipecolic linker
14. Quinolinesulfonamides as potential 5-HT₇ and 5-HT_1A receptor ligands
15. Alkyl-nitroquipazine derivatives as serotonin transporter and 5-HT_1A receptor ligands
16. CHO cell line with stable expression of the HTRA1 gene as a tool for studying functional activity of 5-HT_1A receptor ligands
17. Synthesis of long-chain arylpiperazine theophylline derivatives as potential 5-HT₇ and 5-HT₆ receptors ligands
18. Flexible vs partly constrained linkers in NAN-190 and PK-13 analogs investigated as 5-HT_1A/5-HT₇ receptor ligands
19. Searching for lead molecules as potential new CNS agents in the serotonin 5-HT₆ screening assay
20. Mannich bases, 5-arylimidazolidine-2,4-dione derivatives with arylpiperazine moiety, as 5-HT_1A receptor ligands with serotonin transporter affinity
21. Homology modeling of the 5-HT_1A and 5-HT_2A serotonin receptors on the novel ß₂-adrenergic receptor template
22. Crystal structure of β-adrenergic receptor as a new template in homology modeling of GPCR. Application to serotonin 5-HT_1A and 5-HT₇ receptors
23. Solid-phase synthesis and preliminary biological investigation of arylpiperazine library as 5-HT_1A and 5-HT_2A receptor ligands
24. 2-(1-Arylsulfonylpiperidin-2-yl)ethyl derivatives as 5-HT₇ receptor ligands: synthesis and their affinity for 5-HT_1A/5-HT_2A/5-HT₇/D₂ receptors
25. SAR studies of novel 5-HT₇R ligands with different spacers between aryl and amine moieties
26. Tricyclic theophylline derivatives with arylalkylpiperazinyl moiety as CNS agents
27. Synthesis of novel pyrido[1,2-c]pyrimidine derivatives as selective ligands for 5-HT_1A receptors
28. New serotonin receptors ligands in the group of 8-acylamide derivatives of 1,3-dimethyl-7-[(4-phenyl- piperazin-1-yl)-alkyl]-1H-purine-2,6-(3H,7H)-dione
29. Synthesis and serotonin receptors activity of new purine-2,6-dione derivatives with arylpiperazinylalkoxy moieties
30. Molecular modeling explains differences in binding affinity of new potent and selective 5-HT_1A ligands: arylpiperazinylalkylthiobenzoxazole derivatives
31. The ligand binding to the serotonin transporter
32. NEW DUAL 5-HT₇/5-HT_1A LIGANDS WITH ANTIDEPRESSANT AND ANXIOLYTIC-LIKE ACTIVITY
33. 4,6-DISUBSTITUTED 2-(4-METHYL-1-PIPERA- ZINYL)PYRIDINES: SYNTHESIS AND THEIR BINDING TO SEROTONIN 5-HT_1A, 5-HT_2A, AND 5-HT₇ RECEPTORS
34. ARYLPIPERAZINYLBUTYL DERIVATIVES OF SOME IMIDAZO[2,1-f]THEOPHYLLINE AS CNS RECEPTOR LIGANDS.
35. THE BIOLOGICAL TARGET DERIVED PHARMACOPHORIC MODEL FOR 5-HT₇ SEROTONIN RECEPTOR ANTAGONISM
36. THE STRUCTURE OF AZO-ANALOGS OF 8-STYRYLXANTHINES - X-RAY AND MOLECULAR MODELLING STUDIES
37. SYNTHESIS AND ANTICONVULSANT ACTIVITY OF 4-ARYLPIPERAZINYL METHYL DERIVATIVES OF 5-CYCLOPROPYL-5-PHENYL HYDANTOINS
38. SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF NEW 5,5-DISUBSTITUTED HYDANTOINS
39. SYNTHESIS, IN VITRO AND IN VIVO ACTIVITY OF THE ARYLPIPERAZINYLPROPYL DERIVATIVES OF THE IMIDAZO[2,1-f]THEO- PHYLLINE
40. 8-ALKOXY-PURINE-2,6-DIONES WITH 7-PHENYLPIPERAZINYLALKYL AND 7-TETRAHYDRO-ISOQUINOLINYLALKYL MOIETIES AS 5-HT_1A, 5-HT_2A, 5-HT₇ RECEPTOR LIGANDS