Low-Basicity 5-HT[sub.6] Receptor Ligands from the Group of Cyclic Arylguanidine Derivatives and Their Antiproliferative Activity Evaluation

The serotonin 5-HT[sub.6] receptor (5-HT[sub.6] R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT[sub.6] R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT[sub.6] R l...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-10, Vol.25 (19)
Main Authors: Zareba, Przemyslaw, Drabczyk, Anna K, Wnorowski, Artur, Maj, Maciej, Malarz, Katarzyna, Rurka, Patryk, Latacz, Gniewomir, Duszynska, Beata, Ciura, Krzesimir, Greber, Katarzyna Ewa, Boguszewska-Czubara, Anna, Śliwa, Paweł, Kuliś, Julia
Format: Article
Language:English
Subjects:
Development and progression
Drug therapy
Glioblastoma multiforme
Physiological aspects
Receptors
Serotonin
Serotonin agonists
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Summary:The serotonin 5-HT[sub.6] receptor (5-HT[sub.6] R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT[sub.6] R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT[sub.6] R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT[sub.6] R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug–drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio rerio model. Two antagonists with an affinity constant K [sub.i] < 50 nM (PR 68 K [sub.i] = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug–drug interactions.
ISSN:1422-0067
DOI:10.3390/ijms251910287