RESUMO
The blockade of 5-HT6 receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT6 receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT6 receptors with the specific agonist EMD 386088 (7.4 nM) or the antagonist SB-399885 (300 nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT6 controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABAA receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT6 receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT6 receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT6 receptor antagonists.
Assuntos
Hipocampo , Receptores de Serotonina , Ratos , Animais , Ratos Wistar , Receptores de Serotonina/metabolismo , Células Piramidais/fisiologia , Transmissão Sináptica/fisiologia , Receptores de GABA-ARESUMO
A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (Ki = 58-403 nM), with compound 4d being identified as the most potent ligand. However, regarding C-5 substitution, both methoxy and fluorine were detrimental for receptor affinity compared to our previously published unsubstituted compounds. In order to shed light on these observations, we performed docking and molecular dynamics simulations with the most potent compounds of each series (4d and 4l) and PUC-10, a highly active ligand previously reported by our group. The comparison brings about deeper insight about the influence of the C-5 substitution on the binding mode of the ligands, suggesting that these replacements are detrimental to the affinity due to precluding a ligand from reaching deeper inside the binding site. Additionally, CoMFA/CoMSIA studies were performed to systematize the information of the main structural and physicochemical characteristics of the ligands, which are responsible for their biological activity. The CoMFA and CoMSIA models presented high values of q2 (0.653; 0.692) and r2 (0.879; 0.970), respectively. Although the biological activity of the ligands can be explained in terms of the steric and electronic properties, it depends mainly on the electronic nature.
RESUMO
Alzheimer's Disease (AD) is the most frequent illness and cause of death amongst the age related-neurodegenerative disorders. The Alzheimer's Disease International (ADI) reported in 2019 that over 50 million people were living with dementia in the world and this number could potentially be around 152 million by 2050.5-hydroxtryptamine subtype 6 receptor (5-HT6R) has been identified as a potential anti-amnesic drug target and therefore, the administration of 5-HT6R antagonists can likely mitigate the memory loss and intellectual deterioration associated with AD. Herein, computational tools were applied to design new 5-HT6 antagonists and their biological activity values were predicted by our QSAR model obtained from Artificial Neural Networks (ANN). The proposed compounds here from the QSAR-ANN model presented significant biological activity values and some of them have achieved pKi above 9.00. Furthermore, our results suggest that the presence of halogen atoms (especially bromine) linked to the aromatic ring at para-position (HYD) contribute considerably to the increase of the biological activity values while bulky groups in the PI position do not culminate with the increase antagonist activity of compounds here analyzed. Finally, the ADME/Tox profile as well as the synthetic accessibility of new proposed compounds qualify them to go on further with experimental procedures and thenceforward their antagonist effects can be confirmed.
Assuntos
Desenho de Fármacos , Serotonina , Humanos , Redes Neurais de Computação , Receptores de Serotonina , Antagonistas da Serotonina/farmacologiaRESUMO
To our knowledge the intrahippocampal serotonergic 5-HT6 receptor tone on memory and amnesia models remains unexplored. Hence, in the present work we tested intrahippocampal administration of serotonin or 5-hydroxytryptamine (5-HT)6 receptor experimental molecules with differential intrinsic activity. Methods: In the present study, Automatized Autoshaping memory task was used, useful measuring memory, neural markers, and pharmacological effects. We are hypothesizing that experimental molecules with differential intrinsic activity might reveal serotonergic tone. Particularly, intrahippocampal administration of 5-HT6 receptor compounds with differential intrinsic activity (i.e., agonistic and antagonistic) might evidencing a serotonergic tone via this receptor. Bilateral intrahippocampal dose-response curves show that administration of EMD386088 (10 and 100 µg) had no effect or (50 µg) decreased conditioned responses (CR) in short- and long-term memory (STM and LTM, respectively); while SB-399885 (10 or 100 µg) significantly decreased CR in STM and LTM (24 and 48-h) or (50 µg) had no effect; thus suggesting that there is a 5-HT6 receptor tone regulating both STM and LTM. Moreover, intrahippocampal inactive doses of EMD386088 (5 µg) plus SB-399885 (0.5 µg) did not affect STM and LTM; however, partially or completely prevented the scopolamine or dizocilpine-induced amnesia. Thus confirming that both drugs exerted their effects through 5-HT6 receptor and that there is a hippocampal serotonergic tone under amnesic states, similar to that striatal.
Assuntos
Hipocampo/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Serotoninérgicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Indóis/farmacologia , Masculino , Consolidação da Memória/fisiologia , Memória de Longo Prazo/efeitos dos fármacos , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Piperazinas/farmacologia , Piridinas/farmacologia , Distribuição Aleatória , Ratos Wistar , Sulfonamidas/farmacologiaRESUMO
Based on a known pharmacophore model for 5-HT6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT6 receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay.