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1.
Pharmazie ; 74(3): 131-135, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961676

RESUMO

Propranolol is a popular ß adrenergic antagonists that, together with pindolol, binds also to serotoninergic receptors, namely 5-HT1A/B. In this work the rigidification of the propranolol structure by locking its hydroxyl group within a 1,3-dioxolane ring was investigated. Constrained derivatives of propranolol were synthesized, fully characterized and tested for their affinity at ß-adrenoreceptors and 5-HT1A/B/C receptors using radioligand binding assay. The constrained derivatives were inactive, as expected, at ß1/2/3 adrenergic receptors. Although less expected, these derivatives failed to bind also to 5-HT1A/B/C receptors. The rigidification of propranolol is detrimental for 5-HT1AR activity.


Assuntos
Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/farmacologia , Propranolol/análogos & derivados , Propranolol/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Linhagem Celular , Dioxolanos/química , Humanos , Propranolol/síntese química , Propranolol/química , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Relação Estrutura-Atividade
2.
Neurosci Lett ; 703: 5-10, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30858018

RESUMO

The endocannabinoid system has been implicated in the modulation of behaviors related to anxiety and panic disorders. Accordingly, facilitation of CB1 receptor signaling reduces the consequences of aversive stimuli in animal models. However, the role of the CB1 receptor in the effects of anxiolytic drugs has remained unclear. Here, we tested the hypothesis that the anxiolytic and panicolytic responses to systemic alprazolam injection and local 5-HT1A receptor activation in the dorsolateral periaqueductal gray (dlPAG) depend on CB1 receptor activation. Systemic injection of alprazolam (4 mg/kg) induced an anxiolytic-like effect in the elevated T maze (ETM) model of panic and anxiety, which was prevented by the CB1 antagonist AM251 (0.3 mg/kg). Likewise, intra-dlPAG injection of the 5-HT1A receptor agonist 8-OH-DPAT (3.2 nmol/0.2 u L) also reduced anxiety-like behavior, a response prevented by intra-dlPAG injection of AM251 (100 pmol/0.2 µL). 8-OH-DPAT (8 nmol/0.2 µL) also presented a panicolytic-like activity in the escape reaction induced by chemical stimulation of the dlPAG, which was not prevented by AM251 (100 pmol/0.2 µL). These results suggest that CB1 receptor signaling is involved in the effects of anxiolytic drugs, with potential implications for developing new treatments for anxiety disorders.


Assuntos
Alprazolam/farmacologia , Ansiolíticos/farmacologia , Substância Cinzenta Periaquedutal/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Animais , Ansiedade/psicologia , Reação de Fuga/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Pânico/efeitos dos fármacos , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia
3.
Psychopharmacology (Berl) ; 236(7): 2273-2281, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30903210

RESUMO

RATIONALE: Pre-clinical and clinical studies have suggested that the antidepressant efficacy of escitalopram (ESC) can be augmented by co-administration of aripiprazole (ARI). OBJECTIVE: To establish if the effects of ESC + ARI can be altered by modulating the 5-HT1a receptor. METHODS: Sprague-Dawley male rats received ESC + ARI (10 and 2 mg/kg/day, respectively, via osmotic or by cumulative injections), as well as the 5-HT1a antagonist WAY-100635 (WAY; 0.01-1 mg/kg) and the 5-HT1a agonist 8-OH-DPAT (DPAT; 0.3-1 mg/kg) prior to testing in locomotion chambers and in the forced swim test (FST). Expression of the 5-HT1a receptor mRNA in the dorsal raphe nucleus, hippocampus, septum, and entorhinal cortex was also assessed. RESULTS: WAY generally synergized, while DPAT antagonized, the effect of ESC + ARI on motor activity. All groups showed significantly lower 5-HT1a mRNA in the dorsal raphe nucleus. In the hippocampus, ESC + ARI and WAY + ESC + ARI groups displayed equivalent elevations of 5-HT1a mRNA, but this was not observed in groups that received DPAT + ESC + ARI. Finally, the addition of ARI to ESC augmented the effect that ESC alone had on reducing immobility in the FST. Importantly, WAY antagonized this effect, while DPAT had no consequences. CONCLUSIONS: Taken together, these results in rats indicate that the 5-HT1a receptor is involved in the behavioral and brain region-specific mRNA effects of ESC + ARI.


Assuntos
Aripiprazol/administração & dosagem , Citalopram/administração & dosagem , Receptor 5-HT1A de Serotonina/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Antidepressivos/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Natação/fisiologia , Natação/psicologia
4.
J Neurophysiol ; 121(5): 1591-1608, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30625007

RESUMO

The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI, we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine, and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT1D receptors and not other 5-HT receptors. Selective 5-HT1D receptor antagonists blocked this agonist-induced inhibition, although antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, because normal and injured rats were equally sensitive to 5-HT after SERT was blocked or to agonists not transported by SERT (zolmitriptan). Immunolabeling revealed that the 5-HT1D receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP-positive C-fibers, and eliminated by dorsal rhizotomy. 5-HT1D receptor labeling was not found on large proprioceptive afferents or α-motoneurons of the MSR. Thus serotonergic inhibition of the MSR acts indirectly by modulating C-fiber activity, opening up new possibilities for modulating reflex function and clonus via pain-related pathways. NEW & NOTEWORTHY Brain stem-derived serotonin potently inhibits afferent transmission in the monosynaptic stretch reflex. We show that serotonin produces this inhibition exclusively via 5-HT1D receptors, and yet these receptors are paradoxically mostly confined to C-fibers. This suggests that serotonin acts by gating of C-fiber activity, which in turn modulates afferent transmission to motoneurons. We also show that the classic supersensitivity to 5-HT after spinal cord injury results from a loss of SERT, and not 5-HT1D receptor plasticity.


Assuntos
Fibras Nervosas Amielínicas/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Reflexo de Estiramento , Traumatismos da Medula Espinal/metabolismo , Animais , Feminino , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Ratos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Traumatismos da Medula Espinal/fisiopatologia
5.
Int J Neuropsychopharmacol ; 22(3): 208-220, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445535

RESUMO

BACKGROUND: Most previous studies have focused on the effects of social defeat in male juvenile individuals. Whether chronic social defeat stress in adulthood affects female emotion and the underlying mechanisms remains unclear. METHODS: Using highly aggressive adult female mandarin voles (Microtus mandarinus), the present study aimed to determine the effects of chronic social defeat stress on anxiety- and depression-like behaviors in adult female rodents and investigate the neurobiological mechanisms underlying these effects. RESULTS: Exposure of adult female voles to social defeat stress for 14 days reduced the time spent in the central area of the open field test and in the open arms of the elevated plus maze and lengthened the immobility time in the tail suspension and forced swimming tests, indicating increased anxiety- and depression-like behaviors. Meanwhile, defeated voles exhibited increased neural activity in the prelimbic cortex of the medial prefrontal cortex. Furthermore, chronic social defeat stress reduced serotonin projections and levels of serotonin 1A receptors in the medial prefrontal cortex-prelimbic cortex. Intra-prelimbic cortex microinjections of the serotonin 1A receptor agonist 8-OH-DPAT reversed the alterations in emotional behaviors, whereas injections of the serotonin 1A receptor antagonist WAY-100635 into the prelimbic cortex of control voles increased the levels of anxiety- and depression-like behaviors. CONCLUSIONS: Taken together, our results demonstrated that chronic social defeat stress increased anxiety- and depression-like behaviors in adult female voles, and these effects were mediated by the action of serotonin on the serotonin 1A receptors in the prelimbic cortex. The serotonin system may be a promising target to treat emotional disorders induced by chronic social defeat stress.


Assuntos
Córtex Pré-Frontal/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/metabolismo , Comportamento Social , Estresse Psicológico/metabolismo , Animais , Arvicolinae , Doença Crônica , Feminino , Córtex Pré-Frontal/efeitos dos fármacos , Distribuição Aleatória , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estresse Psicológico/psicologia
6.
J Neurosci ; 39(8): 1484-1504, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30541912

RESUMO

Serotonin (5-hydroxytryptamine, 5-HT) receptor agonists are neuroprotective in CNS injury models. However, the neuroprotective functional implications and synaptic mechanism of 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), a serotonin receptor (5-HT1A) agonist, in an adult male Wistar rat model of chronic glaucoma model remain unknown. We found that ocular hypertension decreased 5-HT1A receptor expression in rat retinas because the number of retinal ganglion cells (RGCs) was significantly reduced in rats with induced ocular hypertension relative to that in control retinas and 8-OH-DPAT enhanced the RGC viability. The protective effects of 8-OH-DPAT were blocked by intravitreal administration of the selective 5-HT1A antagonist WAY-100635 or the selective GABAA receptor antagonist SR95531. Using patch-clamp techniques, spontaneous and miniature GABAergic IPSCs (sIPSCs and mIPSCs, respectively) of RGCs in rat retinal slices were recorded. 8-OH-DPAT significantly increased the frequency and amplitude of GABAergic sIPSCs and mIPSCs in ON- and OFF-type RGCs. Among the signaling cascades mediated by the 5-HT1A receptor, the role of cAMP-protein kinase A (PKA) signaling was investigated. The 8-OH-DPAT-induced changes at the synaptic level were enhanced by PKA inhibition by H-89 and blocked by PKA activation with bucladesine. Furthermore, the density of phosphorylated PKA (p-PKA)/PKA was significantly increased in glaucomatous retinas and 8-OH-DPAT significantly decreased p-PKA/PKA expression, which led to the inhibition of PKA phosphorylation upon relieving neurotransmitter GABA release. These results showed that the activation of 5-HT1A receptors in retinas facilitated presynaptic GABA release functions by suppressing cAMP-PKA signaling and decreasing PKA phosphorylation, which could lead to the de-excitation of RGC circuits and suppress excitotoxic processes in glaucoma.SIGNIFICANCE STATEMENT We found that serotonin (5-HT) receptors in the retina (5-HT1A receptors) were downregulated after intraocular pressure elevation. Patch-clamp recordings demonstrated differences in the frequencies of miniature GABAergic IPSCs (mIPSCs) in ON- and OFF-type retinal ganglion cells (RGCs) and RGCs in normal and glaucomatous retinal slices. Therefore, phosphorylated protein kinase A (PKA) inhibition upon release of the neurotransmitter GABA was eliminated by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), which led to increased levels of GABAergic mIPSCs in ON- and OFF-type RGCs, thus enhancing RGC viability and function. These protective effects were blocked by the GABAA receptor antagonist SR95531 or the 5-HT1A antagonist WAY-100635. This study identified a novel mechanism by which activation of 5-HT1A receptors protects damaged RGCs via the cAMP-PKA signaling pathway that modulates GABAergic presynaptic activity.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , AMP Cíclico/fisiologia , Proteínas do Olho/metabolismo , Glaucoma/metabolismo , Receptor 5-HT1A de Serotonina/fisiologia , Células Ganglionares da Retina/metabolismo , Ácido gama-Aminobutírico/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Bucladesina/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Isoquinolinas/farmacologia , Masculino , Hipertensão Ocular/metabolismo , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Wistar , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Sistemas do Segundo Mensageiro/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sulfonamidas/farmacologia
7.
J Ethnopharmacol ; 231: 453-463, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30545804

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Piper auritum Kunth is employed as an aphrodisiac in the traditional medicine, but corroborative evidence for such effect is scarce. AIM OF THE STUDY: The pro-sexual effect of an aqueous extract of P. auritum and its possible mechanisms were analyzed in two paradigms of male sexual function. MATERIAL AND METHODS: Effects of an aqueous extract of P. auritum (PA, single administration) were investigated in the fictive ejaculation, and copulatory behavior paradigms in sexually sluggish male rats. WAY 100635 (antagonist of 5-HT1A receptors), atosiban (antagonist of oxytocinergic receptors), L-NAME (inhibitor of the nitric oxide synthase) and baclofen (antagonist of GABAB receptors) were used as pre-treatments in order to investigate the role of different neurotransmitter systems in PA actions. Chemical profile of PA was determined by Gases Chromatography and Ultra Performance Chromatography-Electrospray Ionization-Masses Spectrometry (UPLC-ESI-MS). RESULTS: In males with retarded ejaculation, PA stimulated ejaculatory behavior and recovered electromyographic activity of pelvic musculature participating in seminal emission and ejaculation. All pre-treatments blocked stimulating effects of PA on the fictive ejaculation; additionally WAY 100635 interfered with PA actions on ejaculatory behavior. Safrol, apigenin dimethylether, myristicin, vaccihein A, sakuranin and sakuranetin flavonoids, were main constituents of PA, with possible participation in its pro-sexual effects. CONCLUSIONS: Pro-sexual effects of P. auritum elicited at level of ejaculation were mediated by several neurotransmitter systems, among which serotonin and its 5-HT1A receptors play an important role. Present findings support P. auritum reputation as an aphrodisiac, with potential use in delayed ejaculation disorder.


Assuntos
Afrodisíacos/farmacologia , Piper , Extratos Vegetais/farmacologia , Comportamento Sexual/efeitos dos fármacos , Animais , Afrodisíacos/química , Comportamento Animal/efeitos dos fármacos , Ejaculação/efeitos dos fármacos , Feminino , Masculino , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Piper/química , Piperazinas/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Piridinas/farmacologia , Ratos Wistar , Receptor 5-HT1A de Serotonina/fisiologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia
8.
Brain Res ; 1704: 26-39, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30244021

RESUMO

Serotonin (5-HT) has been reported to play excitatory effects on respiration by acting on preBötzinger complex (preBötC) neurons in neonatal or juvenile rodents. However, whether its action is circumscribed to the preBötC and present in other animal species, particularly in adult preparations, is unknown. We investigated the respiratory role of 5-HT within the preBötC and neighbouring respiration-related regions. Experiments were performed on α-chloralose-urethane anesthetized, vagotomized, paralyzed and artificially ventilated rabbits making use of bilateral microinjections (30-50 nl). 5-HT caused excitatory effects on respiratory activity only when applied to the preBötC. These effects were mediated by 5-HT1A and 5-HT3 receptors as shown by microinjections of specific agonists of the different types of 5-HT receptors. Unexpectedly, the blockade of 5-HT1A receptors by methysergide or the specific antagonist (S)-WAY 100135 induced excitatory respiratory effects. Microinjections of the 5-HT3 receptor antagonist ondansetron did not influence respiration, but prevented (S)-WAY 100135-induced responses. The blockade of GABAA receptors by bicuculline within the preBötC prevented the effects of the 5-HT1A receptor agonist 8-OH-DPAT. The involvement of GABAergic inhibition and 5-HT1A receptor-mediated disinhibition is also corroborated by immunohistochemical data. The results show for the first time in an adult animal preparation that 5-HT plays a pivotal role in the modulation of the preBötC activity probably via both presynaptic and postsynaptic mechanisms and highlight the importance of disinhibition phenomena. Present findings may be relevant to some respiratory disorders in which an impairment of central 5-HT mechanisms has been reported, such as sleep apnoea and sudden infant death syndrome.


Assuntos
Neurônios/efeitos dos fármacos , Respiração/efeitos dos fármacos , Centro Respiratório/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT3 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Animais , Masculino , Metisergida/farmacologia , Microinjeções , Ondansetron/farmacologia , Piperazinas/farmacologia , Coelhos
9.
Can J Physiol Pharmacol ; 97(2): 90-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30462556

RESUMO

Although depression and cardiovascular diseases are related, the role of antidepressants such as fluoxetine (increasing serotonin levels) within cardiac regulation remains unclear. We aimed to determine whether fluoxetine modifies the pharmacological profile of serotonergic influence on vagal cardiac outflow. Rats were treated with fluoxetine (10 mg/kg per day; p.o.) for 14 days or equivalent volumes of drinking water (control group); then, they were pithed and prepared for vagal stimulation. Bradycardic responses were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or i.v. acetylcholine (ACh; 1, 5, and 10 µg/kg). The i.v. administration of 5-hydroxytryptamine (5-HT; 10 and 50 µg/kg) inhibited the vagally induced bradycardia. 5-CT (5-HT1/7 agonist) and L-694,247 (5-HT1D agonist) mimicked the serotonin inhibitory effect while α-methyl-5-HT (5-HT2 agonist) was devoid of any action. SB269970 (5-HT7 antagonist) did not abolish 5-CT inhibitory action on the electrically induced bradycardia. Pretreatment with LY310762 (5-HT1D antagonist) blocked the effects induced by L-694,247 and 5-CT. 5-HT and 5-CT failed to modify the bradycardia induced by exogenous ACh. Our outcomes suggest that fluoxetine treatment modifies 5-HT modulation on heart parasympathetic neurotransmission in rats, evoking inhibition of the bradycardia via prejunctional 5-HT1D in pithed rats.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Bradicardia/tratamento farmacológico , Fluoxetina/farmacologia , Receptor 5-HT1D de Serotonina/metabolismo , Nervo Vago/efeitos dos fármacos , Administração Oral , Animais , Antidepressivos de Segunda Geração/uso terapêutico , Bradicardia/etiologia , Depressão/complicações , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fluoxetina/uso terapêutico , Coração/inervação , Frequência Cardíaca/efeitos dos fármacos , Humanos , Oxidiazóis/farmacologia , Fenóis/farmacologia , Ratos , Ratos Wistar , Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/metabolismo , Sulfonamidas/farmacologia , Triptaminas/farmacologia , Nervo Vago/metabolismo
10.
Int J Mol Sci ; 19(10)2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30347827

RESUMO

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.


Assuntos
Carcinogênese/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Células 3T3 , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/farmacologia
11.
Neuropharmacology ; 141: 296-304, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30189184

RESUMO

A single base mutation in the Gαi2 protein (G184S) renders this Gα subunit insensitive to the negative modulatory effects of Regulator of G-protein Signaling (RGS) proteins. Mice expressing this RGS insensitive (RGSi) variant of Gαi2 (RGSi Gαi2) display a spontaneous antidepressant-like phenotype that is reversible by treatment with the 5-HT1A receptor (5-HT1AR) antagonist WAY100635. Here we test the hypothesis that increased activity of 5-HT1ARs in the hippocampus of RGSi Gαi2 knock-in mice is responsible for the expression of the observed antidepressant-like behavior. We administered the 5-HT1AR antagonist WAY100635 or the agonist 8-OH-DPAT via bilateral intra-hippocampal infusion cannulae and evaluated antidepressant-like behavior using the tail suspension test (TST). WAY100635 reversed the antidepressant-like phenotype of the RGSi Gαi2 knock-in mice and 8-OH-DPAT produced an antidepressant-like response in wild type mice that was blocked by systemic WAY100635. Furthermore, intra-hippocampal infusion of the RGS19/4 inhibitor CCG-203769 produced an antidepressant-like effect in female mice. Ex-vivo slice recording confirmed the 5-HT1AR-mediated decrease in hippocampal CA1 pyramidal neuron excitability was enhanced in the RGSi Gαi2 knock-in mice. There was no change in hippocampal 5-HT1AR expression as measured by ligand binding but there was a compensatory reduction in Gαi proteins. The findings demonstrate that RGS protein control of hippocampal 5-HT1AR signaling is necessary and sufficient to account for the antidepressant-like phenotype in the RGSi Gαi2 knock-in mice and that RGS proteins highly expressed in the hippocampus should be investigated as targets for novel antidepressant therapies.


Assuntos
Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Hipocampo/metabolismo , Resposta de Imobilidade Tônica/fisiologia , Proteínas RGS/antagonistas & inibidores , Receptor 5-HT1A de Serotonina/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/antagonistas & inibidores , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Feminino , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/genética , Técnicas de Introdução de Genes , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Microinjeções , Fenótipo , Piperazinas/farmacologia , Células Piramidais/fisiologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/biossíntese , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia
12.
Neuropharmacology ; 141: 139-147, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30170082

RESUMO

Serotonin (5-HT) neurons are strongly implicated in mood disorders such as depression and are importantly regulated by feedback inhibition mediated by 5-HT1A receptors. These receptors may play a role, albeit a poorly understood one, in the generation of mood disorders, treatment response to antidepressants and delayed therapeutic efficacy. Here we sought to gain insight into the role of 5-HT1A receptor-mediated feedback inhibition in these processes by studying Fos protein expression within serotonin neurons in a rat model of stress-related mood disorder, early life maternal separation (MS), combined with two-week treatment with the antidepressant fluoxetine (FLX) in adulthood. We gauged 5-HT1A receptor-mediated feedback inhibition by the ability of the antagonist, WAY-100635 (WAY), to disinhibit Fos expression in 5-HT neurons. We found that two-week FLX treatment dramatically inhibited Fos expression in serotonin neurons and that this effect was reversed by blocking 5-HT1A receptors with WAY. Together these observations reveal that after prolonged exposure to SSRIs, endogenous 5-HT1A receptors continue to exert feedback inhibition of serotonin neurons. Furthermore we found unique effects of pharmacological treatments after MS in that the WAY effect was greatest in MS rats treated with FLX, a phenomenon selective to the rostral 2/3 of the dorsal raphe nucleus (B7). These results indicate that the balance between activation and feedback inhibition of serotonin neurons in B7 is altered and uniquely sensitive to FLX after early-life stress.


Assuntos
Retroalimentação Fisiológica/fisiologia , Fluoxetina/farmacologia , Privação Materna , Proteínas Proto-Oncogênicas c-fos/biossíntese , Receptor 5-HT1A de Serotonina/fisiologia , Neurônios Serotoninérgicos/fisiologia , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Masculino , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia
13.
Physiol Behav ; 196: 119-125, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30179595

RESUMO

Low frequency stimulation (LFS) has been proposed as a method in the treatment of epilepsy, but its anticonvulsant mechanism is still unknown. In the current study, the hippocampal CA1 region was microinjected with NAD-299 (a selective 5-HT1A antagonist), and its role in mediating the inhibitory action of LFS on amygdala kindling was investigated. Male Wistar rats were kindled by amygdala stimulation in a semi-rapid kindling manner (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, 50-150 µA) was applied at 5 min after termination of daily kindling stimulations. NAD (a selective 5-HT1A antagonist) was microinjected into the CA1 region of the hippocampus at the doses of 2.5 and 5 µg/1 µl. An open field test was also run to determine the motor activity of animals in different experimental groups. The application of LFS following daily kindling stimulations reduced the behavioral seizure stages, afterdischarge duration, and stage 5 seizure duration and increased the latency to stage 4 seizure compared to the kindled group. However, microinjection of NAD at the doses of 5 µg/1 µl, but not 2.5 µg/1 µl, blocked the inhibitory effect of LFS on behavioral and electrophysiological parameters in kindled animals. It could be presumed that 5-HT1A receptors in the CA1 area are involved in mediating the antiepileptic effects of LFS.


Assuntos
Região CA1 Hipocampal/metabolismo , Terapia por Estimulação Elétrica , Receptor 5-HT1A de Serotonina/metabolismo , Convulsões/metabolismo , Convulsões/terapia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Benzopiranos/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Neuroestimuladores Implantáveis , Excitação Neurológica , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos Wistar , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia
14.
Expert Opin Ther Pat ; 28(9): 679-689, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30124346

RESUMO

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/metabolismo
15.
Br J Pharmacol ; 175(16): 3369-3378, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29859012

RESUMO

BACKGROUND AND PURPOSE: The aim of this study was to explore if the administration of naltrexone together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately. EXPERIMENTAL APPROACH: The effects of low doses of naltrexone (0.7 mg·kg-1 , p.o.) and/or CBD (20 mg·kg-1 ·day-1 , s.c.) on ethanol consumption and motivation to drink were evaluated in the oral-ethanol self-administration paradigm in C57BL/6 mice. Gene expression analyses of the opioid µ receptor (Oprm1) in the nucleus accumbens (NAc), tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and the 5-HT1A receptor in the dorsal raphe nucleus (DR) were carried out by real-time PCR. The role of 5-HT1A receptors in the ethanol reduction induced by the administration of CBD + naltrexone was analysed by using the 5-HT1A receptor antagonist WAY100635 (0.3 mg·kg-1 , i.p.). KEY RESULTS: The administration of CBD + naltrexone significantly reduced motivation and ethanol intake in the oral self-administration procedure in a greater proportion than the drugs given alone. Only the combination of both drugs significantly reduced Oprm1, TH and 5-HT1A gene expressions in the NAc, VTA and DR respectively. Interestingly, the administration of WAY100635 significantly blocked the actions of CBD + naltrexone but had no effects by itself. CONCLUSION AND IMPLICATIONS: The combination of low doses of CBD plus naltrexone were more effective than either CBD or naltrexone alone at reducing ethanol consumption and the motivation to drink. These effects appear to be mediated, at least in part, by 5-HT1A receptors.


Assuntos
Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Canabidiol/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptor 5-HT1A de Serotonina/genética , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Motivação/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores Opioides mu/genética , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
16.
Biomed Pharmacother ; 103: 546-552, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29677541

RESUMO

The piperazine derivatives correspond to an extensive chemical class of compounds with numerous neuropharmacological activities, including antidepressant (e.g., nefazodone, trazodone) and anxiolytic (e.g., buspirone) properties. Therefore, aiming to identify a new antidepressant and antianxiety lead-compound, our group designed, synthesized, and investigated the effects of a new piperazine compound, namely, LQFM104, on the behavior of mice. Male albino Swiss mice were treated with LQFM104 prior to predictive behavioral tests as open field (OFT), elevated plus maze (EPM), forced swimming (FST), and tail suspension tests (TST). The participation of the serotonergic system was evaluated by pretreatment with a 5-HT1A antagonist receptor (WAY100635) and serotonin (5-HT) synthesis inhibitor (p-chlorphenylalanine, pCPA) before oral administration of LQFM104 and behavioral tests. The treatment with LQFM104 did not interfere with locomotor activity but revealed suggestive data of anxiolytic-like effects by the increase in the time spent in the center of the OFT. This activity was confirmed by the results obtained in the EPM, and it was abolished after pretreatment with WAY100635 and pCPA. The immobility time decreased in both the FST and TST. The antidepressant-like activity was completely abolished after WAY100635 pretreatment. Altogether, these data revealed that LQFM104 possesses anxiolytic and antidepressant-like properties in behavioral tests on mice, and these activities are possibly mediated, directly and/or indirectly, by serotonergic pathways.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Piperazinas/farmacologia , Receptor 5-HT1A de Serotonina/fisiologia , Serotonina/fisiologia , Animais , Ansiolíticos/química , Antidepressivos/química , Relação Dose-Resposta a Droga , Elevação dos Membros Posteriores/métodos , Elevação dos Membros Posteriores/psicologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Piperazina , Piperazinas/química , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia
17.
Behav Pharmacol ; 29(5): 437-444, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29521667

RESUMO

The present study investigated the effects of estradiol (E2) on ingestive behavior after activation of 5-HT1A receptors in the lateral hypothalamus (LH) of female rats habituated to eat a wet mash diet. Ovariectomized rats treated with corn oil (OVX) or estradiol cypionate (OVX+E) received local injections into the LH of vehicle or an agonist of 5-HT1A receptors, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; at a dose of 6 nmol). To determine the involvement of these receptors in food intake, some animals were pretreated with N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY-100635, a 5-HT1A receptor full antagonist, at a dose of 0.37 nmol), followed by the injection of the agonist 8-OH-DPAT or its vehicle. The results showed that the injection of 8-OH-DPAT into the LH of OVX rats significantly increased food intake, and the duration and frequency of this behavior. The pretreatment with E2 suppressed the hyperphagic response induced by 8-OH-DPAT in OVX animals. The inhibition of 5-HT1A receptors after pretreatment with WAY-100635 blocked the hyperphagic effects evoked by 8-OH-DPAT in OVX. These results indicate that the activity of LH 5-HT1A receptors could be affected by blood E2 levels.


Assuntos
Estradiol/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/metabolismo , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/efeitos dos fármacos , Ovariectomia , Piperazinas , Piridinas , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
18.
Neuropharmacology ; 135: 22-33, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29510186

RESUMO

Repeated injections of cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, attenuate the anxiogenic effects induced by Chronic Unpredictable Stress (CUS). The specific mechanisms remain to be fully understood but seem to involve adult hippocampal neurogenesis and recruitment of endocannabinoids. Here we investigated for the first time if the behavioral and pro-neurogenic effects of CBD administered concomitant the CUS procedure (14 days) are mediated by CB1, CB2 or 5HT1A receptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3ß and the synaptic proteins Synapsin Ia/b, mGluR1 and PSD95). After 14 days, CBD injections (30 mg/kg) induced anxiolytic responses in stressed animals in the elevated plus-maze and novelty suppressed feeding tests, that were blocked by pre-treatment with a CB1 (AM251, 0.3 mg/kg) or CB2 (AM630, 0.3 mg/kg), but not by a 5HT1A (WAY100635, 0.05 mg/kg) receptor antagonist. Golgi staining and immunofluorescence revealed that these effects were associated with an increase in hippocampal neurogenesis and spine density in the dentate gyrus of the hippocampus. AM251 and AM630 abolished the effects of CBD on spines density. However, AM630 was more effective in attenuating the pro-neurogenic effects of CBD. CBD decreased FAAH and increased p-GSK3ß expression in stressed animals, which was also attenuated by AM630. These results indicate that CBD prevents the behavioral effects caused by CUS probably due to a facilitation of endocannabinoid neurotransmission and consequent CB1/CB2 receptors activation, which could recruit intracellular/synaptic proteins involved in neurogenesis and dendritic remodeling.


Assuntos
Canabidiol/farmacologia , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Estresse Psicológico/prevenção & controle , Amidoidrolases/metabolismo , Animais , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/citologia , Indóis/farmacologia , Masculino , Camundongos , Piperazinas , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-akt , Pirazóis/farmacologia , Piridinas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Estresse Psicológico/metabolismo , Sinapsinas/metabolismo
19.
FASEB J ; 32(6): 3193-3214, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29430989

RESUMO

Substance P (SP) is a candidate mediator along the brain-skin axis and can mimic the effects of stress to regulate melanogenesis. Previously, we and others have found that the regulation of SP for pigmentary function was mediated by neurokinin 1 receptor (NK1R). Emerging evidence has accumulated that psychologic stress can induce dysfunction in the cutaneous serotonin 5-hydroxytryptamine (5-HT)-5-HT1A/1B receptor system, thereby resulting in skin hypopigmentation. Moreover, NK1R and 5-HTR (except 5-HT3) belong to GPCR. The present study aimed at assessing the possible existence of NK1R-5-HTR interactions and related melanogenic functions. Western blot and PCR detection revealed that SP reduced expression of 5-HT1A receptor via the NK1 receptor. Biochemical analyses showed that NK1R and 5-HT1AR could colocalize and interact in a cell and in the skin. When the N terminus of the NK1R protein was removed NK1R surface targeting was prevented, the interaction between NK1R-5-HT1AR decreased, and the depigmentation caused by SP and WAY100635 could be rescued. Importantly, pharmaceutical coadministration of NK1R agonist (SP) and 5-HT1A antagonist (WAY100635) enhanced the NK1-5-HT1A receptor coimmunoprecipitation along with the depigmentary response. SP and WAY100635 cooperation elicited activation of a signaling cascade (the extracellular, regulated protein kinase p-JNK signaling pathway) and inhibition of p70S6K1 phosphorylation and greatly reduced melanin production in vitro and in vivo in mice and zebrafish. Moreover, the SP-induced depigmentation response did not be occur in 5-htr1aa+/- zebrafish embryos. Taken together, the results of our systemic study increases our knowledge of the roles of NK1R and 5-HT1AR in melanogenesis and provides possible, novel therapeutic strategies for treatment of skin hypo/hyperpigmentation.-Wu, H., Zhao, Y., Huang, Q., Cai, M., Pan, Q., Fu, M., An, X., Xia, Z., Liu, M., Jin, Y., He, L., Shang, J. NK1R/5-HT1AR interaction is related to the regulation of melanogenesis.


Assuntos
Melaninas/biossíntese , Receptor 5-HT1A de Serotonina/metabolismo , Receptores da Neurocinina-1/metabolismo , Pigmentação da Pele , Pele/metabolismo , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Melaninas/genética , Camundongos , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/genética , Receptores da Neurocinina-1/genética , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Pele/patologia , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Substância P/metabolismo , Substância P/farmacologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
20.
Bioorg Med Chem Lett ; 28(4): 606-611, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29395980

RESUMO

In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D2, serotonin 5-HT1A and 5-HT2A receptors, but also exhibited low potency for α1A, H1 and 5-HT2C receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain. Furthermore, 7h exhibited more potent antipsychotic-like effect than aripiprazole in behavioral studies. The preliminary results were promising enough for further research around this scaffold.


Assuntos
Antipsicóticos/farmacologia , Ácidos Picolínicos/farmacologia , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/metabolismo , Aripiprazol/farmacologia , Antagonistas dos Receptores de Dopamina D2/síntese química , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Humanos , Masculino , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ácidos Picolínicos/metabolismo , Risperidona/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade
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