RESUMO
There is some evidence that the serotonin receptor subtype 7 (5-HT7) could be new therapeutic target for neuroprotection. The aim of this study was to compare the neuroprotective and neurite outgrowth potential of new 5-HT7 receptor agonists (AH-494, AGH-238, AGH-194) with 5-CT (5-carboxyamidotryptamine) in human neuroblastoma SH-SY5Y cells. The results revealed that 5-HT7 mRNA expression was significantly higher in retinoic acid (RA)-differentiated cells when compared to undifferentiated ones and it was higher in cell cultured in neuroblastoma experimental medium (DMEM) compared to those placed in neuronal (NB) medium. Furthermore, the safety profile of compounds was favorable for all tested compounds at concentration used for neuroprotection evaluation (up to 1 µM), whereas at higher concentrations (above 10 µM) the one of the tested compounds, AGH-194 appeared to be cytotoxic. While we observed relatively modest protective effects of 5-CT and AH-494 in UN-SH-SY5Y cells cultured in DMEM, in UN-SH-SY5Y cells cultured in NB medium we found a significant reduction of H2O2-evoked cell damage by all tested 5-HT7 agonists. However, 5-HT7-mediated neuroprotection was not associated with inhibition of caspase-3 activity and was not observed in RA-SH-SY5Y cells exposed to H2O2. Furthermore, none of the tested 5-HT7 agonists altered the damage induced by 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium ion (MPP +) and doxorubicin (Dox) in UN- and RA-SH-SY5Y cells cultured in NB. Finally we showed a stimulating effect of AH-494 and AGH-194 on neurite outgrowth. The obtained results provide insight into neuroprotective and neurite outgrowth potential of new 5-HT7 agonists.
Assuntos
Neuroblastoma , Crescimento Neuronal , Fármacos Neuroprotetores , Receptores de Serotonina , Agonistas do Receptor de Serotonina , Humanos , Receptores de Serotonina/metabolismo , Fármacos Neuroprotetores/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Linhagem Celular Tumoral , Neuroblastoma/patologia , Neuroblastoma/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sobrevivência Celular/efeitos dos fármacos , Serotonina/análogos & derivadosRESUMO
Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.
Assuntos
Antipsicóticos , Quinazolinonas , Receptores de Glutamato Metabotrópico , Esquizofrenia , Animais , Humanos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Maleato de Dizocilpina , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Desenho de FármacosRESUMO
A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.
Assuntos
Antipsicóticos/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Indóis/farmacologia , Nootrópicos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/farmacologia , Animais , Antipsicóticos/síntese química , Família 2 do Citocromo P450/metabolismo , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/síntese química , Células Hep G2 , Humanos , Indóis/síntese química , Ligantes , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Nootrópicos/síntese química , Ligação Proteica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologia , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Relação Estrutura-Atividade , Triptaminas/síntese químicaRESUMO
RATIONALE: Our study aimed to unravel the unknown mechanisms behind the exceptional efficacy of Psilocybin (PSI) in treating treatment-resistant depression (TRD). Focusing on Wistar-Kyoto (WKY) rats with a TRD phenotype and Wistar (WIS) rats as a normative comparison, we investigated behavioral and neuroplasticity-related responses to PSI, striving to shed light on the distinctive features of its antidepressant effects. OBJECTIVES: We set out to assess the behavioral impact of acute and prolonged PSI administration on WKY and WIS rats, employing Novel Object Recognition (NORT), Social Interaction (SI), and Forced Swimming Test (FST). Our secondary objectives involved exploring strain-specific alterations in neuroplasticity-related parameters, including brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc). METHODS: Conducting post-acute and extended assessments after a single PSI administration, we applied behavioral tests and biochemical analyses to measure serum BDNF levels and neuroplasticity-related parameters in the prefrontal cortex. Statistical analyses were deployed to discern significant differences between the rat strains and assess the impact of PSI on behavioral and biochemical outcomes. RESULTS: Our findings uncovered significant behavioral disparities between WKY and WIS rats, indicating passive behavior and social withdrawal in the former. PSI demonstrated pronounced pro-social and antidepressant effects in both strains, each with its distinctive temporal trajectory. Notably, we identified strain-specific variations in BDNF-related signaling and observed the modulation of Arc expression in WKY rats. CONCLUSIONS: Our study delineated mood-related behavioral nuances between WKY and WIS rat strains, underscoring the antidepressant and pro-social properties of PSI in both groups. The distinct temporal patterns of observed changes and the identified strain-specific neuroplasticity alterations provide valuable insights into the TRD phenotype and the mechanisms underpinning the efficacy of PSI.
RESUMO
RATIONALE: Ketamine and psilocybin belong to the rapid-acting antidepressants but they also produce psychotomimetic effects including timing distortion. It is currently debatable whether these are essential for their therapeutic actions. As depressed patients report that the "time is dragging," we hypothesized that ketamine and psilocybin-like compounds may produce an opposite effect, i.e., time underestimation, purportedly contributing to their therapeutic properties. OBJECTIVES: Timing was tested following administration of (R)- and (S)-ketamine, and psilocybin, psilocin, and norpsilocin in the discrete-trial temporal discrimination task (TDT) in male rats. Timing related to premature responses, and cognitive and unspecific effects of compounds were tested in the 5-choice serial reaction time task (5-CSRTT) in the standard 1-s, and "easier" 2-s stimulus duration conditions, as well as in the vITI variant promoting impulsive responses. RESULTS: (S)-ketamine (15 but not 3.75 or 7.5 mg/kg) shifted psychometric curve to the right in TDT and reduced premature responses in 5-CSRTT, suggesting expected time underestimation, but it also decreased the accuracy of temporal discrimination and increased response and reward latencies, decreased correct responses, and increased incorrect responses. While (R)-ketamine did not affect timing and produced no unspecific actions, it reduced incorrect responses in TDT and increased accuracy in 5-CSRTT, suggesting pro-cognitive effects. Psilocin and psilocybin produced mainly unspecific effects in both tasks, while norpsilocin showed no effects. CONCLUSIONS: Time underestimation produced by (S)-ketamine could be associated with its antidepressant effects; however, it was accompanied with severe behavioral disruption. We also hypothesize that behavioral disruption produced by psychedelics objectively reflects their psychotomimetic-like actions.
Assuntos
Ketamina , Psilocibina , Animais , Antidepressivos/farmacologia , Cognição , Humanos , Ketamina/farmacologia , Masculino , Psilocibina/análogos & derivados , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Ratos , Serotonina/análogos & derivadosRESUMO
Major depressive disorder is a complex disease resulting from aberrant synaptic plasticity that may be caused by abnormal serotonergic signaling. Using a combination of behavioral, biochemical, and imaging methods, we analyze 5-HT7R/MMP-9 signaling and dendritic spine plasticity in the hippocampus in mice treated with the selective 5-HT7R agonist (LP-211) and in a model of chronic unpredictable stress (CUS)-induced depressive-like behavior. We show that acute 5-HT7R activation induces depressive-like behavior in mice in an MMP-9-dependent manner and that post mortem brain samples from human individuals with depression reveal increased MMP-9 enzymatic activity in the hippocampus. Both pharmacological activation of 5-HT7R and modulation of its downstream effectors as a result of CUS lead to dendritic spine elongation and decreased spine density in this region. Overall, the 5-HT7R/MMP-9 pathway is specifically activated in the CA1 subregion of the hippocampus during chronic stress and is crucial for inducing depressive-like behavior.
Assuntos
Região CA1 Hipocampal , Transtorno Depressivo Maior , Animais , Região CA1 Hipocampal/metabolismo , Transtorno Depressivo Maior/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Receptores de Serotonina/metabolismoRESUMO
Hydrogen bonds (HBs) directly engaging fluorine has been extensively studied, but the indirect effect of fluorine on adjacent donors and acceptors is poorly understood and still difficult to predict. The indirect and direct effect of the fluorination of aniline on HB patterns observed in monofluoroanilines was studied via experimental (vibrational spectroscopy and crystal structure analysis) and theoretical (ab initio molecular dynamics and electrostatic surface potential) methods. It was found that a fluorine substituent decreases the strength and frequency of N-Hâ¯N HBs and, at the same time, increases the acidity of CH protons, enhancing the competitiveness of weaker interactions. Additionally, the position of fluorine in the aromatic ring strongly affects the C-F bond length, and a direct intramolecular N-Hâ¯F HB causes an increase in the N-H bond stability. We also provide a methodology to identify and separate individual HBs concerning the type of donor or acceptor from the ab initio molecular dynamics trajectories.
RESUMO
The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. 'XSAR library analysis', a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.
Assuntos
Fluoxetina/farmacologia , Fluvoxamina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Dose-Resposta a Droga , Fluoxetina/síntese química , Fluoxetina/química , Fluvoxamina/síntese química , Fluvoxamina/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
Among all of the monoaminergic receptors, the 5-HT6R has the highest number of non-basic ligands (approximately 5% of compounds stored in 25th version of ChEMBL database have the strongest basic pKa below 5, calculated using the Instant JChem calculator plugin). These compounds, when devoid of a basic nitrogen, exhibit high affinity and remarkable selectivity. Despite a decade of research, no clues have been given for explanation of such an intriguing phenomenon. Here, a series of analogs of four known 5-HT6R ligands, has been rationally designed to approach this issue. For each of the synthesized 42 compounds, a binding affinity for 5-HT6R has been measured, together with a selectivity profile against 5-HT1AR, 5-HT2AR, 5-HT7R and D2R. Performed induced fit docking and molecular dynamics experiments revealed that no particular interaction was responsible for the activity of non-basic compounds. In fact, a plain N-phenylsulfonylindole (1e) was found to possess a moderate (5-HT6R, Ki = 159 nM) affinity. No other monoaminergic receptor has as simple and selective ligand as this one. Thus, it is stated that it binds to the receptor solely based on its conformation and as such, possesses a minimum amount of features, required for binding. Also, any functional group able to form an additional interaction with the receptor increase the binding affinity, like in the case of two highly active non-basic compounds 3e and 5g (5-HT6R, Ki = 65 nM and 38 nM, respectively).
Assuntos
Desenho de Fármacos , Indóis/química , Receptores de Serotonina/metabolismo , Células HEK293 , Humanos , Indóis/metabolismo , Indóis/farmacologia , Ligantes , Simulação de Dinâmica Molecular , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans.
Assuntos
Cognição/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/química , Ketamina/farmacologia , Animais , Relação Dose-Resposta a Droga , Função Executiva/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , EstereoisomerismoRESUMO
A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Kiâ¯=â¯91â¯nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Kiâ¯=â¯25, 5-HT2AR Kiâ¯=â¯32â¯nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.
Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Triptaminas/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Células Hep G2 , Humanos , Ligantes , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química , Células Tumorais CultivadasRESUMO
PURPOSE: Like other psychedelics, D-lysergic acid diethylamide (LSD) affects numerous serotonin receptors, and according to the current dogma, the 5-HT2A receptors are considered the main target for its hallucinogenic effects. LSD, however, also displays agonistic activity at the 5-HT5A receptors, which mediate some of LSD-induced behavioural effects. METHODS: Using male Sprague Dawley rats, we examined the effects of 5-HT2A and 5-HT5A receptor antagonists on LSD-induced stimulus control in the two-lever drug discrimination test using a FR10 schedule of reinforcement. RESULTS: In animals trained to discriminate 0.08 mg/kg LSD from vehicle 15 minutes after injection, LSD produced dose-related increases in response, with an ED50 (±95% confidence limits) of 0.0384 (± 0.025-0.051) mg/kg). LSD-like responses were observed when the training dose of LSD was given 5-30 but not 90 minutes before the test. Confirming earlier reports, the 5-HT antagonist ketanserin (2 mg/kg) attenuated the LSD response in 50% of rats, and due to pretreatment with 0.2 and 2 mg/kg MDL 100907, 63% and 67% of animals, respectively, failed to select the LSD lever. We then investigated the effects of two 5-HT5A receptor antagonists, and we found that 56% and 60% of rats pretreated with 3 and 10 mg/kg SB 699551, respectively, failed to select the LSD lever. Due to pretreatment with 0.01 mg/kg ASP 5736, 58% of rats did not select the LSD lever. This dose also reduced the response rate but not the number of rats failing to complete the test. CONCLUSIONS: The present results suggest that antagonists of the 5-HT5A receptor may inhibit subjective effects of LSD in rats.
Assuntos
Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Animais , Sinais (Psicologia) , Aprendizagem por Discriminação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Alucinógenos/administração & dosagem , Ketanserina/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/administração & dosagemRESUMO
A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT6R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT6R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT6R and very high selectivity over 5-HT1A, 5-HT2A, 5-HT7 and D2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Desenho de Fármacos , Imidazóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Células Cultivadas , Disfunção Cognitiva/induzido quimicamente , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Escopolamina/administração & dosagem , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-AtividadeRESUMO
The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7Râ¯=â¯4â¯nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmaxâ¯=â¯1069â¯ng/g were found after i.p. (2.5â¯mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.
Assuntos
Imidazóis/química , Imidazóis/farmacocinética , Indóis/química , Indóis/farmacocinética , Neuralgia/tratamento farmacológico , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Células HEK293 , Halogenação , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Indóis/administração & dosagem , Indóis/uso terapêutico , Masculino , Camundongos , Modelos Moleculares , Neuralgia/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/uso terapêuticoRESUMO
INTRODUCTION: 5-HT1AR was one of the first discovered serotonin receptors and is one of the most thoroughly studied. Dysfunctions associated with 5-HT1AR neurotransmission are linked to several psychiatric disorders, including anxiety, depression, and movement disorders. AREAS COVERED: The current review covers patent literature published between January 2012 and May 2018. Queries were performed on Espacenet, SciFinder, clinicaltrials.gov, pharmacodia.com, and the websites of pharmaceutical companies. EXPERT OPINION: Several novel therapeutic applications have been proposed for 5-HT1AR ligands, i.e. prostate cancer treatment, gastrointestinal and cardiopulmonary disorders, facilitation of urination and defecation, and L-DOPA-induced dyskinesia. Interestingly, no patent application has been filed by big pharma companies, while numerous researches are being conducted in smaller companies and academia.
Assuntos
Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Desenho de Fármacos , Humanos , Ligantes , Patentes como Assunto , Receptor 5-HT1A de Serotonina/metabolismoRESUMO
The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C-Hâ¯O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.
RESUMO
Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT7 receptor agonist of higher selectivity. In vitro drug-likeness studies and in vivo pharmacological evaluation of potent and selective low-basicity 5-HT7 receptor agonists, previously published 7 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide, AH-494) and 13 (3-(1-methyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive in vitro comparison studies between 7, 13 and the commonly used 5-CT showed their very similar ADMET properties. Compound 7 at 1 mg kg-1 reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both in vitro and in vivo data, 7 and 13 may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HT1AR.
RESUMO
A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC50 values of 0.86, 1.05, and 0.85 µM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both best cytotoxic and antitubulin activity, were further studied in terms of their effect on cell cycle distribution and proapoptotic activity. Compound 23e induced a statistically significant block of the cell cycle at the G2/M phase in A431, HaCaT, HeLa, MCF-7, MDA-MB-231, and SKOV-3 cells to an extent comparable to that observed in CA-4. In HeLa and SKOV-3 cells incubated with 23i, a concentration-dependent block of the G2/M phase was observed. The proapoptotic effect of 23e and 23i in A431, HaCaT, MCF-7, MDA-MB-231, and SKOV-3 was demonstrated with ELISA assay and double staining with Annexin V-FITC/PI. The results indicated that compound 23e and 23i may serve as novel lead compounds in research on more effective anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Microtúbulos/efeitos dos fármacos , Estilbenos/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Combinatória , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
In this letter, we report the synthesis of a pyrano[2,3,4-cd]indole chemical scaffold designed through a tandem bioisostere generation/virtual screening protocol in search of 5-HT6R ligands. The discovered chemical scaffold resulted in the design of highly active basic and nonbasic 5-HT6R ligands (5-HT6R Ki = 1 nM for basic compound 6b and 5-HT6R Ki = 4 nM for its neutral analog 7b). Additionally, molecular modeling suggested that the hydroxyl group of nonbasic ligands 7a-7d forms hydrogen bonds with aspartic acid D3×32 or D7.36×35.