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1.
Eur J Med Chem ; 236: 114329, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35397400

RESUMO

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease.


Assuntos
Inibidores da Monoaminoxidase , Quinolinas , Animais , Encéfalo/metabolismo , Flúor/farmacologia , Camundongos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Quinolinas/metabolismo , Ratos
2.
ACS Chem Neurosci ; 12(7): 1228-1240, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33705101

RESUMO

Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound's activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists.


Assuntos
Pirróis , Receptores de Serotonina , Animais , Cognição , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade
3.
Pharmacol Biochem Behav ; 203: 173152, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33577868

RESUMO

R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (marketed as Spravato for depression). Recent data have suggested (R)-ketamine could have value in the treatment of substance use disorder. The present set of experiments was undertaken to examine whether (R)-ketamine might prevent tolerance development. Rapid ethanol (ETOH) tolerance was studied since racemic ketamine had previously been shown to block this tolerance development in rats. In the present study, male Sprague-Dawley rats were given two large doses of ETOH on Day 1 (2.3 + 1.7 g/kg) and 2.3 g/kg ETOH on Day 2. Animals were tested for effects of 2.3 g/kg ETOH on grip strength, inclined screen performance and rotarod performance on Day 1 with or without (R)-ketamine as a pretreatment. (R)-ketamine alone was tested at the highest dose studied (10 mg/kg) and did not significantly influence any dependent measure. (R)-ketamine (1-10 mg/kg) did not alter the acute effects of ETOH except for enhancing the effects of ETOH on the inclined screen test at 3 mg/kg. Between-subjects analysis documented that tolerance developed to the effects of ETOH only on the measure of grip strength. (R)-ketamine (3 mg/kg) given prior to ETOH on Day 1 exhibited a strong trend toward preventing tolerance development (p = 0.062). The present results extend prior findings on the potential value of (R)-ketamine in substance abuse disorder therapeutics and add to the literature on NMDA receptor blockade as a tolerance-regulating mechanism.


Assuntos
Alcoolismo/tratamento farmacológico , Tolerância a Medicamentos , Etanol/administração & dosagem , Ketamina/administração & dosagem , Ketamina/química , Animais , Comportamento Animal/efeitos dos fármacos , Força da Mão , Isomerismo , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
4.
J Med Chem ; 64(2): 1180-1196, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33439019

RESUMO

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/prevenção & controle , Masculino , Conformação Molecular , Neuritos/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 208: 112765, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949963

RESUMO

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT6R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.


Assuntos
Alcinos/farmacologia , Indóis/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Receptores de Serotonina/metabolismo , Alcinos/síntese química , Alcinos/farmacocinética , Animais , Astrócitos/efeitos dos fármacos , Linhagem Celular Tumoral , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacocinética , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Nootrópicos/síntese química , Nootrópicos/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacocinética , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade
7.
Pharmacol Rep ; 72(3): 589-599, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32207091

RESUMO

RATIONALE: The α4ß2 nicotinic acetylcholine receptors (α4ß2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4ß2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4ß2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized. OBJECTIVES: The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4ß2-nAChR PAM. METHODS: Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats. RESULTS: The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-ß-erythroidine, a relatively selective α4ß2-nAChR antagonist, indicating the involvement of α4ß2-nAChRs in cognitive processes. The tested α4ß2-PAM was also effective against ketamine- and scopolamine-induced deficits of object recognition memory. Moreover, procognitive effects were also observed after combined treatment with inactive doses of dFBr and TC-2403, a selective α4ß2-nAChR agonist. CONCLUSIONS: These findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4ß2-nAChR potentiation as a plausible therapy for cognitive impairment.


Assuntos
Atenção/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Hidrocarbonetos Bromados/farmacologia , Alcaloides Indólicos/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos , Reconhecimento Psicológico/efeitos dos fármacos , Regulação Alostérica , Animais , Disfunção Cognitiva/induzido quimicamente , Ketamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Escopolamina/farmacologia
8.
Behav Brain Res ; 385: 112547, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32087183

RESUMO

Positive allosteric modulators (PAMs) of alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) may represent a novel approach to attenuate cognitive decline in Alzheimer's disease (AD). One possible scenario for the use of this class of compounds is their combination with currently approved anti-AD drugs. We thus evaluated the efficacy of co-administration of inactive doses of type I and type II α7-nAChR PAMs (CCMI and PNU-120596, respectively) with acetylcholinesterase inhibitors (AChEIs), donepezil and galantamine, or with a non-competitive glutamate N-methyl-D-aspartate receptor antagonist, memantine, in ameliorating scopolamine-induced memory deficits in the novel object recognition test in rats. Both CCMI and PNU-120596 as well as donepezil, galantamine and memantine attenuated the scopolamine-induced recognition impairments. Interestingly, the combined administration of previously established sub-effective doses of the tested PAMs (0.1 mg/kg) with either AChEIs, donepezil (0.3 mg/kg) and galantamine (0.1 mg/kg), or memantine (0.3 mg/kg) also restored object recognition memory in scopolamine-treated animals. These findings suggest the therapeutic potential of α7-nAChR PAMs as an augmentation strategy for cognitive enhancement in AD.


Assuntos
Inibidores da Colinesterase/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Isoxazóis/farmacologia , Compostos de Fenilureia/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Regulação Alostérica , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Antagonistas Colinérgicos/toxicidade , Modelos Animais de Doenças , Donepezila/farmacologia , Sinergismo Farmacológico , Galantamina/farmacologia , Memantina/farmacologia , Nootrópicos/farmacologia , Ratos , Escopolamina/toxicidade
9.
Eur J Med Chem ; 185: 111857, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734022

RESUMO

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 Ki = 91 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 Ki = 25, 5-HT2AR Ki = 32 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 Cultivadas
10.
Mol Neurobiol ; 57(3): 1733-1747, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31823199

RESUMO

Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies. Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics. We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg). Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFß1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC. The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.


Assuntos
Antipsicóticos/farmacologia , Canabidiol/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Ketamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Sprague-Dawley , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo
11.
J Psychopharmacol ; 33(11): 1447-1455, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31452444

RESUMO

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 & dosagem
12.
Eur J Med Chem ; 179: 1-15, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31229883

RESUMO

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-Atividade
13.
ACS Chem Neurosci ; 10(7): 3183-3196, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30896921

RESUMO

In light of the multifactorial origin of neurodegenerative disorders and some body of evidence indicating that pharmacological blockade of serotonin 5-HT6 and dopamine D3 receptors might be beneficial for cognitive decline, we envisioned (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (CPPQ), a neutral antagonist of 5-HT6R, as a chemical template for designing dual antagonists of 5-HT6/D3 receptors. As shown by in vitro experiments, supported by quantum chemical calculations and molecular dynamic simulations, introducing alkyl substituents at the pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 5-HT6 and D3 receptors. The study identified compound 19 ((S)-1-((3-chlorophenyl)sulfonyl)-N-(1-isobutylpyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine), which was classified as a dual 5-HT6/D3R antagonist (Ki(5-HT6) = 27 nM, Ki(D3) = 7 nM). Compound 19 behaved as a neutral antagonist at Gs signaling and had no influence on receptor-operated, cyclin-dependent kinase 5 (Cdk5)-dependent neurite growth. In contrast to the well characterized 5-HT6R antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicin, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into procognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats.


Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Antagonistas da Serotonina/farmacologia , Astrócitos/efeitos dos fármacos , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 25(10): 2789-2799, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28391970

RESUMO

A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT7R antagonists. Among the compounds evaluated herein, 3-chloro-N-{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide (25) exhibited antagonistic properties at 5-HT7R and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.625-2.5mg/kg, i.p.) and in the tail suspension test (1.25mg/kg, i.p.), augmented the antidepressant effect of inactive doses of escitalopram (selective serotonin reuptake inhibitor) and bupropion (dopamine reuptake inhibitor) in the FST in mice, and similarly to SB-269970, exerted pro-cognitive properties in the novel object recognition task in cognitively unimpaired conditions in rats (0.3mg/kg, i.p.). Such an extended pharmacological profile, especially the augmentation effect of the identified 5-HT7R antagonist on SSRI activity, seems promising regarding the complexity of affective disorders and potentially improved outcomes, including mnemonic performance.


Assuntos
Antidepressivos/química , Inibidores da Captação de Dopamina/química , Piperidinas/química , Receptores de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/química , Sulfonamidas/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Células CHO , Cognição/efeitos dos fármacos , Cricetinae , Cricetulus , Inibidores da Captação de Dopamina/farmacologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fenóis/farmacologia , Estrutura Terciária de Proteína , Ratos , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia
15.
J Pharmacol Exp Ther ; 321(3): 1208-25, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17325229

RESUMO

Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine > serotonin > dopamine (approximately 1:2:17). This in vitro profile is supported by microdialysis studies in freely moving rats, where bicifadine (20 mg/kg i.p.) increased extrasynaptic norepinephrine and serotonin levels in the prefrontal cortex, norepinephrine levels in the locus coeruleus, and dopamine levels in the striatum. Orally administered bicifadine is an effective antinociceptive in several models of acute, persistent, and chronic pain. Bicifadine potently suppressed pain responses in both the Randall-Selitto and kaolin models of acute inflammatory pain and in the phenyl-p-quinone-induced and colonic distension models of persistent visceral pain. Unlike many transport inhibitors, bicifadine was potent and completely efficacious in both phases of the formalin test in both rats and mice. Bicifadine also normalized the nociceptive threshold in the complete Freund's adjuvant model of persistent inflammatory pain and suppressed mechanical and thermal hyperalgesia and mechanical allodynia in the spinal nerve ligation model of chronic neuropathic pain. Mechanical hyperalgesia was also reduced by bicifadine in the streptozotocin model of neuropathic pain. Administration of the D(2) receptor antagonist (-)-sulpiride reduced the effects of bicifadine in the mechanical hyperalgesia assessment in rats with spinal nerve ligations. These results indicate that bicifadine is a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models, with activation of dopaminergic pathways contributing to its antihyperalgesic actions.


Assuntos
Analgésicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dor/tratamento farmacológico , Doença Aguda , Analgésicos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Doença Crônica , Desipramina/farmacologia , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Microdiálise , Atividade Motora/efeitos dos fármacos , Proteínas de Transporte de Neurotransmissores/antagonistas & inibidores , Proteínas de Transporte de Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Dor/metabolismo , Dor/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Receptores de Neurotransmissores/antagonistas & inibidores , Receptores de Neurotransmissores/metabolismo , Serotonina/metabolismo
16.
J Pharmacol Exp Ther ; 319(3): 1244-52, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16971504

RESUMO

Studies using mice with point mutations of GABA(A) receptor alpha subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA(A) receptors bearing the alpha(1) and alpha(2) subunits. This hypothesis predicts that a compound with high efficacy at GABA(A) receptors containing the alpha(1) subunit would produce sedation, whereas an agonist acting at alpha(2) subunit-containing receptors (with low or null efficacy at alpha(1)-containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA(A) receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at alpha(1)beta(2)gamma(2S) constructs of the GABA(A) receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing alpha(2), alpha(3), or alpha(5) subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test, an effect blocked by flumazenil, and increased the percentage of time spent in the open arms of the elevated plus-maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than 1 order of magnitude greater than the minimal effective anxiolytic dose. Although the mutant mouse data predict that the high-efficacy potentiation of GABA(A1a) receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by alpha(1) subunit-containing GABA(A) receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.


Assuntos
Ansiolíticos/farmacologia , Canais de Cloreto/metabolismo , Diazepam/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/fisiologia , Animais , Ansiolíticos/síntese química , Ataxia/induzido quimicamente , Ataxia/patologia , Canais de Cloreto/efeitos dos fármacos , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Força da Mão/fisiologia , Hipnóticos e Sedativos/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Oócitos/metabolismo , Equilíbrio Postural/efeitos dos fármacos , Pirazóis/síntese química , Piridinas/síntese química , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Xenopus laevis
17.
Cell Mol Neurobiol ; 26(4-6): 857-73, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16636898

RESUMO

1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dopamina/fisiologia , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/fisiologia , Receptores de Neurotransmissores/antagonistas & inibidores , Serotonina/fisiologia , Aclimatação/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar
18.
Pharmacol Rep ; 58(6): 836-45, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17220541

RESUMO

Following our behavioral studies demonstrating augmentation of imipramine action by concomitant administration of nicotine, we investigated the effects of one or 14 days of treatment (twice daily) with imipramine and nicotine on dopamine metabolism in various brain areas of rat and noradrenaline in the brain stem. In addition, we evaluated the responses of this metabolism to apomorphine challenge in the rat. Generally, chronic treatment of imipramine and nicotine produced opposite effects to acute administration. As revealed by HPLC, dopamine metabolism in the nucleus accumbens was slightly decreased after 14 days of treatment with imipramine, and co-administration of nicotine resulted in a significant and much more pronounced depression of dopamine metabolism in all investigated dopaminergic structures. Such biochemical effects suggested the development of a compensatory mechanism related with hypersensitivity of dopamine D(2) receptors in the mesolimbic and nigrostriatal system. Chronic administration of imipramine produced an opposite effect to the acute one in the brain stem noradrenergic system, like it was observed in dopaminergic structures. Significant inhibition of noradrenaline metabolism after acute administration of imipramine may be explained by its inhibitory effect on noradrenaline reuptake process. In contrast, chronic imipramine administration had no effect on noradrenaline metabolism what indicated the development of subsensitivity of (2)-adrenoceptors in the brain stem responsible for the rate of noradrenaline metabolism. Apomorphine alone decreased metabolism of both catecholamine, dopamine and noradrenaline through activation of dopamine D(2) receptors which are located also on noradrenergic neurons. The biochemical response to apomorphine in terms of dopamine metabolism was not changed by chronic administration of the investigated drugs but noradrenaline metabolism in the brain stem was strongly attenuated after a combined treatment of imipramine and nicotine. The present data demonstrate facilitation and potentiation of biochemical antidepressant-like effects of imipramine by nicotine co-treatment. We suggest that nicotine may potentiate the antidepressant-like effects of imipramine by promoting some plastic changes in the brain within dopamine and noradrenaline system considerably more strongly than imipramine alone.


Assuntos
Antidepressivos/farmacologia , Dopamina/metabolismo , Imipramina/farmacologia , Nicotina/farmacologia , Norepinefrina/metabolismo , Animais , Apomorfina/farmacologia , Sinergismo Farmacológico , Ácido Homovanílico/análise , Masculino , Metoxi-Hidroxifenilglicol/análise , Ratos , Ratos Wistar
19.
Eur J Pharmacol ; 515(1-3): 128-33, 2005 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-15893747

RESUMO

Converging lines of evidence indicate the involvement of nicotinic acetylcholine receptors in depressive illness and antidepressant drug action. We investigated the effects of sub-chronic and chronic treatment with imipramine, nicotine and their combination on: (a) the ability of a dopamine-mimetic challenge to produce locomotor stimulation and (b) cortical density of beta-adrenoceptors. One week of treatment with imipramine (10 mg/kg, twice daily) did not result in an altered response to the apomorphine (0.15 mg/kg) challenge, but after 2 weeks, the imipramine-treated rats demonstrated hyperactivity. Conversely, such increased locomotor response was observed in rats treated with nicotine (0.4 mg/kg, twice daily) for 1 but not for 2 weeks. Groups treated with nicotine+imipramine for 1 and 2 weeks demonstrated equally high hyperactivity in response to the apomorphine challenge. This effect was not different from the effects of 1-week treatment with nicotine or 2-week treatment with imipramine. The density of beta-adrenoceptors was equally decreased by 2 (but not 1) weeks of the treatment with imipramine, nicotine and their combination. The present behavioral and neurochemical data suggest the antidepressant-like effect of the chronic treatment with nicotine. It appears that the potentiation of the dopamine-mimetic-induced hyperactivity cannot be explained by beta-adrenoceptor down-regulation.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Nicotina/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Análise de Variância , Animais , Apomorfina/farmacologia , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Imipramina/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismo , Fatores de Tempo
20.
Br J Pharmacol ; 139(6): 1196-202, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12871839

RESUMO

1. Epidemiological and clinical observations suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in depressive illness. Nonetheless, there is no clearcut evidence that nicotine and/or nAChR antagonists produce an antidepressant effect. 2. In the tail-suspension test (C57/Bl male mice), nicotine (0.8-1.2 mg kg(-1) s.c. or i.p.) given 15-60 min before the measurement exerted no effect on immobility. 3. Given 30 min before the measurement, citalopram (2 mg kg(-1)) produced a slight decrease in immobility; coadministration of nicotine (0.8 mg kg(-1), 15 but not 40 min before the test) to citalopram-treated mice resulted in a robust decrease in immobility. Imipramine (4 mg kg(-1)) did not affect immobility, but given in combination with 0.8 mg kg(-1) of nicotine (15 but not 40 min before the test), a decrease in immobility was observed. Nicotine (0.8 and 1.2 mg kg(-1)) also produced an enhancement in the anti-immobility effect of imipramine (20 mg kg(-1)). 4. We further investigated if nAChR antagonists would influence the antidepressant-like effects of imipramine and citalopram. Unexpectedly, mecamylamine (1-2.5 mg kg(-1)) and dihydro-beta-erythroidine (2 mg kg(-1)) potentiated the antidepressant-like effect of imipramine (4-20 mg kg(-1)). Mecamylamine (2.5 mg kg(-1)) but not dihydro-beta-erythroidine also increased the antidepressant-like effect produced by 2 mg kg(-1) of citalopram. 5. The interaction between nAChR antagonists and antidepressants appeared synergistic. 6. Neither nAChR ligands, antidepressants nor combinations of the two, affected locomotor activity. 7. The present results demonstrate an unexpected interaction between nAChR ligands and imipramine and citalopram in the tail-suspension test.


Assuntos
Antidepressivos/farmacologia , Citalopram/farmacologia , Imipramina/farmacologia , Nicotina/farmacologia , Antagonistas Nicotínicos/farmacologia , Animais , Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Sinergismo Farmacológico , Elevação dos Membros Posteriores/fisiologia , Imipramina/uso terapêutico , Imobilização/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nicotina/uso terapêutico , Antagonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/fisiologia
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