However, some of the compounds (2, 3 and 12) behaved similarly to combined agonistCantagonists, exhibiting antagonistic activity within the cAMP pathway and agonistic activity within the ERK1/2 pathway

However, some of the compounds (2, 3 and 12) behaved similarly to combined agonistCantagonists, exhibiting antagonistic activity within the cAMP pathway and agonistic activity within the ERK1/2 pathway. agonistic or antagonistic activity on both the cAMP and MAPK/ERK pathways (Table 3). However, SRT 1460 some of themAB22 (8), paroxetine (2) and Ac-paroxetine (3)behaved much like combined agonistsCantagonists, exhibiting antagonistic activity within the cAMP pathway and agonistic activity SRT 1460 within the MAPK/ERK pathway. Table 3 Functional activity of fresh and classic ligands of 5-HT1A receptor in HEK293 cells that overexpress the gene. gene, it was found that “type”:”entrez-protein”,”attrs”:S14506″S14506 acted like a cAMP pathway agonist (dose-dependently diminishing cAMP levels, EC50 = 25.4 pM) and a MAPK/ERK1/2 pathway agonist (elevating phosphorylated ERK1/2 levels, EC50 = 93.0 pM) (Number 5 and Number 6). It should be mentioned, however, that “type”:”entrez-protein”,”attrs”:S14506″S14506 was found to be an Akt pathway antagonist in HEK293 cells that overexpress the gene (Number 7). Akt may activate nuclear translocation of NF-B, leading to caspase-3 inhibition and cell survival. The prosurvival activity of Akt may be reversed by Akt antagonists [9,10]. Consequently, the antagonistic activity of “type”:”entrez-protein”,”attrs”:S14506″S14506 on Akt may induce caspase-3 activity and cytotoxicity. Open in a separate window Number 5 Influence of “type”:”entrez-protein”,”attrs”:S14506″S14506 within the (1 M) forskolin-stimulated cAMP level in HEK293 cells that overexpress the gene. Open in a separate window Number 6 Influence of “type”:”entrez-protein”,”attrs”:S14506″S14506 on pERK1/2 level in HEK293 cells that overexpress the gene. Open in a separate window Number 7 Influence of “type”:”entrez-protein”,”attrs”:S14506″S14506 on pAkt level in HEK293 cells that overexpress the gene. The cytotoxic activity of “type”:”entrez-protein”,”attrs”:S14506″S14506 against prostate malignancy Personal computer-3 cells (but not against neuroblastoma SH-SY5Y cells, Number 8 and Number 9) was reversed by treatment with the 5-HT1A receptor antagonist WAY100635 and inverse agonist spiperone. Open in a separate window Number 8 Cytotoxicity of “type”:”entrez-protein”,”attrs”:S14506″S14506 on Personal computer-3 cells in the presence of WAY100635 (5 M) and spiperone (5 M). * < 0.05 vs. control. Open in a separate window Number 9 Cytotoxicity of "type":"entrez-protein","attrs":S14506"S14506 on NH-SY5Y cells in the presence of WAY100635 (5 M) and spiperone (5 M). It was also found that "type":"entrez-protein","attrs":S14506"S14506 triggered the cAMP biochemical pathway in Personal computer-3 cells (IC50 SRT 1460 = 0.32 M, Number 10) but not in SH-SY5Y cells. Open in a separate window Number 10 Influence of "type":"entrez-protein","attrs":S14506"S14506 within the cAMP level in Personal computer-3 prostate malignancy cells (1 M forskolin). Compound "type":"entrez-protein","attrs":S14506"S14506, although structurally related to the 5-HT1A receptor inverse agonist spiperone, has been found to be probably one of the most potent agonists of the receptor, with very high affinity (Kd = 0.79 0.2 nM, compared to 8-OH-DPAT Kd = 1.5 0.5 nM). Additionally, the affinity of "type":"entrez-protein","attrs":S14506"S14506 (but not of 8-OH-DPAT) was reduced by divalent manganese, magnesium and calcium ions. The presence of sodium ions markedly reduced the binding of 8-OH-DPAT but not the binding of "type":"entrez-protein","attrs":S14506"S14506 [11]. "type":"entrez-protein","attrs":S14506"S14506 potently reduced the duration of immobility in the pressured swim test in rats in the minimal effective dose (MED) 0.01 mg/kg, s.c. (MED for 8-OH-DPAT was 0.63 mg/kg). The action of "type":"entrez-protein","attrs":S14506"S14506 was clogged from SRT 1460 the 5-HT1A receptor antagonist WAY100135. It was proposed the antidepressant action of the compound is definitely conveyed by postsynaptic 5-HT1A receptors [12]. It was also found that compound "type":"entrez-protein","attrs":S14506"S14506 exhibited the properties SRT 1460 of a dopamine D2 receptor antagonist [13]. 2.2. Molecular Modelling After docking, the ligands (buspirone, "type":"entrez-protein","attrs":S14506"S14506, PLAU and spiperone) bound in a similar mode to the pocket created by transmembrane helices (TM): TM3, TM5, TM6 and TM7 (Number 11). The binding energies for buspirone, “type”:”entrez-protein”,”attrs”:S14506″S14506 and spiperone were related: ?19.46, ?22.46 and ?21.21 kcal/mol, respectively. The charged piperazine nitrogen atom of the compounds interacted with.