Abstract:5-HT 1A receptor is one of the most important members of the numerous families of serotoninergic receptors. Though it was the first 5-HT receptor to be identified and cloned, the knowledge of its activation/transduction mechanisms, mediated effects, and connection with other systems is still uncompleted. For this reason, relevant is the study of the four Ws of the title: first of all "who" this receptor is, then "why" it continues to be a so attractive target after several years after its identification, then … Show more
“…Mechanistically, almost all of them act as agonists (partial/full) of 5-HT 1A R, and two main interactions proved to be important for the affinity of arylpiperazines toward 5-HT 1A Rs: (a) an ionic bond between the protonated nitrogen atom of the piperazine ring and the carboxyl oxygen of the side chain of Asp3.32 and (b) an edge-to-face CH/π interaction between the aromatic ring and the Phe6.52 residue, which stabilizes the ligand binding [6]. The basic pharmacophore of the 5-HT 1A R ligands is the same for agonists and antagonists and consists of an aromatic nucleus and a basic nitrogen atom, whose optimal distance is 5.2 Å, while the nitrogen lies at 0.2 Å above the plane defined by the reference ring [7]. Moreover, arylpiperazine derivatives have been described to reduce prostate cancer cell growth [8] and to ameliorate sensitivity to Tamoxifen in ER+ BC cells [4].…”
Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a–c) and the corresponding acetylated derivatives was used (3a–c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a–c) and corresponding N-acetyl derivatives (3a–c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a–c and 3a–c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.
“…Mechanistically, almost all of them act as agonists (partial/full) of 5-HT 1A R, and two main interactions proved to be important for the affinity of arylpiperazines toward 5-HT 1A Rs: (a) an ionic bond between the protonated nitrogen atom of the piperazine ring and the carboxyl oxygen of the side chain of Asp3.32 and (b) an edge-to-face CH/π interaction between the aromatic ring and the Phe6.52 residue, which stabilizes the ligand binding [6]. The basic pharmacophore of the 5-HT 1A R ligands is the same for agonists and antagonists and consists of an aromatic nucleus and a basic nitrogen atom, whose optimal distance is 5.2 Å, while the nitrogen lies at 0.2 Å above the plane defined by the reference ring [7]. Moreover, arylpiperazine derivatives have been described to reduce prostate cancer cell growth [8] and to ameliorate sensitivity to Tamoxifen in ER+ BC cells [4].…”
Arylpiperazines represent one of the most important classes of 5-HT1AR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (2a–c) and the corresponding acetylated derivatives was used (3a–c). The new compounds were tested for their functional activity and affinity at 5-HT1A receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound 2b. The cytotoxic activity of novel thiazolinylphenyl-piperazines (2a–c) and corresponding N-acetyl derivatives (3a–c) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for 2a–c and 3a–c compounds (IC50 values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.
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