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1.
Bioorg Med Chem Lett ; 30(9): 127066, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32173198

RESUMO

Antagonism of the mGluR2 receptor has the potential to provide therapeutic benefit to cognitive disorders by elevating synaptic glutamate, the primary excitatory neurotransmitter in the brain. Selective antagonism of the mGluR2 receptor, however, has so far been elusive, given the very high homology of this receptor with mGluR3, particularly at the orthosteric binding site. Given that inhibition of mGluR3 has been implicated in undesired effects, we sought to identify selective mGluR2 negative allosteric modulators. Herein we describe the discovery of the highly potent and selective class of mGluR2 negative allosteric modulators, 4-arylquinoline-2-carboxamides, following a successful HTS campaign and medicinal chemistry optimization, showing potent in vivo efficacy in rodent.

2.
J Pharmacol Exp Ther ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094294

RESUMO

Treatments for cognitive deficits associated with CNS disorders such as Alzheimer's disease (AD) and schizophrenia remain significant unmet medical needs that incur substantial pressure on the healthcare system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine (ACh)-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation (LTP) of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nAChR PAM that potentiates ACh-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in CNS diseases with cognitive impairments.

3.
ACS Med Chem Lett ; 9(8): 815-820, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30128073

RESUMO

Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

4.
PLoS One ; 13(6): e0198395, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29870538

RESUMO

Studies in rodents show that olfactory processing in the principal neurons of olfactory bulb (OB) and piriform cortex (PC) is controlled by local inhibitory interneurons, and glutamate NMDA receptor plays a role in this inhibitory control. It is not clear if findings from studies in rodents translate to olfactory processing in nonhuman primates (NHPs). In this study, the effect of the glutamate NMDA receptor antagonist MK801 on odorant-induced olfactory responses in the OB and PC of anesthetized NHPs (rhesus monkeys) was investigated by cerebral blood volume (CBV) fMRI. Isoamyl-acetate was used as the odor stimulant. For each NHP, sixty fMRI measurements were made during a 4-h period, with each 4-min measurement consisting of a 1-min baseline period, a 1-min odor stimulation period, and a 2-min recovery period. MK801 (0.3 mg/kg) was intravenously delivered 1 hour after starting fMRI. Before MK801 injection, olfactory fMRI activations were observed only in the OB, not in the PC. After MK801 injection, olfactory fMRI activations in the OB increased, and robust olfactory fMRI activations were observed in the PC. The data indicate that MK801 enhances the olfactory responses in both the OB and PC. The enhancement effects of MK801 are most likely from its blockage of NMDA receptors on local inhibitory interneurons and the attenuation of the inhibition onto principal neurons. This study suggests that the mechanism of local inhibitory control of principal neurons in the OB and PC derived from studies in rodents translates to NHPs.


Assuntos
Imagem por Ressonância Magnética/métodos , Bulbo Olfatório/diagnóstico por imagem , Córtex Olfatório/diagnóstico por imagem , Percepção Olfatória/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Volume Sanguíneo Cerebral , Maleato de Dizocilpina/farmacologia , Feminino , Macaca mulatta , Bulbo Olfatório/metabolismo , Córtex Olfatório/metabolismo , Pentanóis/farmacologia
5.
J Pain Res ; 11: 735-741, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29692626

RESUMO

Introduction: The development of novel analgesics to treat acute or chronic pain has been a challenge due to a lack of translatable measurements. Preclinical end points with improved translatability are necessary to more accurately inform clinical testing paradigms, which may help guide selection of viable drug candidates. Methods: In this study, a nonhuman primate biomarker which is sensitive to standard analgesics at clinically relevant plasma concentrations, can differentiate analgesia from sedation and utilizes a protocol very similar to that which can be employed in human clinical studies is described. Specifically, acute heat stimuli were delivered to the volar forearm using a contact heat thermode in the same manner as the clinical setting. Results: Clinically efficacious exposures of morphine, fentanyl, and tramadol produced robust analgesic effects, whereas doses of diazepam that produce sedation had no effect. Conclusion: We propose that this assay has predictive utility that can help improve the probability of success for developing novel analgesics.

6.
PLoS One ; 13(4): e0195486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29624602

RESUMO

Although tau pathology, behavioral deficits, and neuronal loss are observed in patients with tauopathies, the relationship between these endpoints has not been clearly established. Here we found that rTg4510 mice, which overexpress human mutant tau in the forebrain, develop progressive age-dependent increases in locomotor activity (LMA), which correlates with neurofibrillary tangle (NFT) pathology, hyperphosphorylated tau levels, and brain atrophy. To further clarify the relationship between these endpoints, we treated the rTg4510 mice with either doxycycline to reduce mutant tau expression or an O-GlcNAcase inhibitor Thiamet G, which has been shown to ameliorate tau pathology in animal models. We found that both doxycycline and Thiamet G treatments starting at 2 months of age prevented the progression of hyperactivity, slowed brain atrophy, and reduced brain hyperphosphorylated tau. In contrast, initiating doxycycline treatment at 4 months reduced neither brain hyperphosphorylated tau nor hyperactivity, further confirming the relationship between these measures. Collectively, our results demonstrate a unique behavioral phenotype in the rTg4510 mouse model of tauopathy that strongly correlates with disease progression, and that early interventions which reduce tau pathology ameliorate the progression of the locomotor dysfunction. These findings suggest that better understanding the relationship between locomotor deficits and tau pathology in the rTg4510 model may improve our understanding of the mechanisms underlying behavioral disturbances in patients with tauopathies.


Assuntos
Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Progressão da Doença , Doxiciclina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Atividade Motora/genética , Atividade Motora/fisiologia , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Piranos/uso terapêutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tauopatias/patologia , Tauopatias/fisiopatologia , Tiazóis/uso terapêutico , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Proteínas tau/genética
7.
Bioorg Med Chem Lett ; 28(6): 1122-1126, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29534798

RESUMO

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.


Assuntos
Ácido Acético/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Indóis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Ácido Acético/síntese química , Ácido Acético/química , Animais , Domínio Catalítico/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Relação Estrutura-Atividade
8.
J Pharmacol Exp Ther ; 365(3): 556-566, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29563325

RESUMO

The current standard of care for treating Alzheimer's disease is acetylcholinesterase inhibitors, which nonselectively increase cholinergic signaling by indirectly enhancing activity of nicotinic and muscarinic receptors. These drugs improve cognitive function in patients, but also produce unwanted side effects that limit their efficacy. In an effort to selectively improve cognition and avoid the cholinergic side effects associated with the standard of care, various efforts have been aimed at developing selective M1 muscarinic receptor activators. In this work, we describe the preclinical and clinical pharmacodynamic effects of the M1 muscarinic receptor-positive allosteric modulator, MK-7622. MK-7622 attenuated the cognitive-impairing effects of the muscarinic receptor antagonist scopolamine and altered quantitative electroencephalography (qEEG) in both rhesus macaque and human. For both scopolamine reversal and qEEG, the effective exposures were similar between species. However, across species the minimum effective exposures to attenuate the scopolamine impairment were lower than for qEEG. Additionally, there were differences in the spectral power changes produced by MK-7622 in rhesus versus human. In sum, these results are the first to demonstrate translation of preclinical cognition and target modulation to clinical effects in humans for a selective M1 muscarinic receptor-positive allosteric modulator.


Assuntos
Quinazolinas/farmacologia , Receptor Muscarínico M1/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Humanos , Macaca mulatta , Masculino , Quinazolinas/farmacocinética , Pesquisa Médica Translacional
9.
Neurobiol Aging ; 64: 92-106, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29353102

RESUMO

While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.


Assuntos
Envelhecimento , Doença de Alzheimer/genética , Cognição/fisiologia , Modelos Animais de Doenças , Envelhecimento/líquido cefalorraquidiano , Envelhecimento/genética , Envelhecimento/patologia , Envelhecimento/psicologia , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Feminino , Humanos , Masculino , Emaranhados Neurofibrilares/patologia , Córtex Pré-Frontal/fisiopatologia , Proteínas tau/líquido cefalorraquidiano
10.
J Neurochem ; 142(2): 204-214, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28444767

RESUMO

Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)A receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects. Given their distinct mechanism of action, the current work tested the hypothesis that DORAs and GABAA receptor modulators differentially regulate neurochemical pathways associated with differences in sleep architecture and cognitive performance induced by these pharmacological mechanisms. Our findings showed that DORA-22 suppresses the release of the wake neurotransmitter histamine in the lateral hypothalamus, prefrontal cortex, and hippocampus with no significant alterations in acetylcholine levels. In contrast, eszopiclone, commonly used as a GABAA modulator, inhibited acetylcholine secretion across brain regions with variable effects on histamine release depending on the extent of wakefulness induction. In normal waking rats, eszopiclone only transiently suppressed histamine secretion, whereas this suppression was more obvious under caffeine-induced wakefulness. Compared with the GABAA modulator eszopiclone, DORA-22 elicits a neurotransmitter profile consistent with wake reduction that does not impinge on neurotransmitter levels associated with cognition and rapid eye movement sleep.


Assuntos
Acetilcolina/metabolismo , Hipocampo/efeitos dos fármacos , Histamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Triazóis/farmacologia , Animais , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Sono/efeitos dos fármacos , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Vigília/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia
11.
Neuroimage ; 149: 348-360, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28163142

RESUMO

Olfactory adaptation, characterized by attenuation of response to repeated odor stimulations or continuous odor exposure, is an intrinsic feature of olfactory processing. Adaptation can be induced by either "synaptic depression" due to depletion of neurotransmitters, or "enhanced inhibition" onto principle neurons by local inhibitory interneurons in olfactory structures. It is not clear which mechanism plays a major role in olfactory adaptation. More importantly, molecular sources of enhanced inhibition have not been identified. In this study, olfactory responses to either repeated 40-s stimulations with interstimulus intervals (ISI) of 140-s or 30-min, or a single prolonged 200-s stimulus were measured by fMRI in different naïve rats. Olfactory adaptations in the olfactory bulb (OB), anterior olfactory nucleus (AON), and piriform cortex (PC) were observed only with repeated 40-s odor stimulations, and no olfactory adaptations were detected during the prolonged 200-s stimulation. Interestingly, in responses to repeated 40-s odor stimulations in the PC, the first odor stimulation induced positive activations, and odor stimulations under adapted condition induced negative activations. The negative activations suggest that "sparse coding" and "global inhibition" are the characteristics of olfactory processing in PC, and the global inhibition manifests only under an adapted condition, not a naïve condition. Further, we found that these adaptations were NMDA receptor dependent; an NMDA receptor antagonist (MK801) blocked the adaptations. Based on the mechanism that glutamate NMDA receptor plays a role in the inhibition onto principle neurons by interneurons, our data suggest that the olfactory adaptations are caused by enhanced inhibition from interneurons. Combined with the necessity of the interruption of odor stimulation to observe the adaptations, the molecular source for the enhanced inhibition is most likely an increased glutamate release from presynaptic terminals due to glutamate over-replenishment during the interruption of odor stimulation. Furthermore, with blockage of the adaptations, the data reveal that orbital, medial & prefrontal, and cingulate cortices (OmPFC) are involved in the olfactory processing.


Assuntos
Adaptação Fisiológica/fisiologia , Bulbo Olfatório/fisiologia , Percepção Olfatória/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Adaptação Fisiológica/efeitos dos fármacos , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Imagem por Ressonância Magnética , Ratos , Ratos Sprague-Dawley
12.
Psychopharmacology (Berl) ; 233(13): 2441-50, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27117142

RESUMO

RATIONALE: Much preclinical data, almost exclusively using rodent, supports the notion that phosphodiesterase 10A (PDE10A) inhibition may offer an alternative to the current standard of care in schizophrenia. However, concerns persist regarding the clinical translatability of these models for newer drug classes like PDE10A inhibitors. OBJECTIVES: We therefore sought to characterize the clinical standard risperidone and the PDE10A inhibitor THPP-1 in nonhuman primate, both alone and when used as a combination therapy. METHODS: THPP-1 and risperidone were tested in a novel rhesus model of stimulant-induced motor activity (SIMA) and in rhesus electroencephalography (EEG). RESULTS: Consistent with rodent data, both THPP-1 and risperidone significantly attenuated the stimulant effects in SIMA when administered alone, though some differences were noted. Combination therapy with a low dose of risperidone produced significantly more robust effects. THPP-1 and risperidone also produced a marked reduction of wake cycle time and gamma frequency power in EEG. However, THPP-1 differed from risperidone by reducing spectral power of lower frequencies (delta). CONCLUSIONS: SIMA results suggest that PDE10A inhibition produces antipsychotic-like effects in higher species, and that combination therapy with PDE10A inhibitors may produce more robust efficacy compared to monotherapies. EEG and qEEG results confirm that PDE10A inhibition does share some central signaling effects with clinically effective antipsychotics. The present combination therapy results may carry implications for the manner in which clinical testing of PDE10A inhibitors is conducted.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/farmacologia , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Análise de Variância , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Macaca mulatta , Masculino , Atividade Motora/efeitos dos fármacos
13.
J Med Chem ; 59(7): 3489-98, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-27011007

RESUMO

Herein, we describe the development of a functionally selective liver X receptor ß (LXRß) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-ß peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/líquido cefalorraquidiano , Benzamidas/química , Benzamidas/farmacologia , Receptores Nucleares Órfãos/agonistas , Piperidinas/química , Piperidinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Células Hep G2 , Humanos , Lipídeos/análise , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Locomoção/efeitos dos fármacos , Macaca mulatta , Células Madin Darby de Rim Canino , Camundongos , Camundongos Transgênicos
14.
Sleep ; 39(3): 603-12, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26943466

RESUMO

STUDY OBJECTIVES: In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening. METHODS: DORA-22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n = 34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened. RESULTS: All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened. CONCLUSIONS: In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action.


Assuntos
Macaca mulatta/fisiologia , Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologia , Animais , Nível de Alerta/efeitos dos fármacos , Condicionamento Clássico , Estudos Cross-Over , Diazepam/farmacologia , Zopiclona/farmacologia , GABAérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Masculino , Piperidinas/farmacologia , Polissonografia , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Triazóis/farmacologia
15.
ACS Med Chem Lett ; 7(3): 312-7, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985321

RESUMO

Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.

16.
Bioorg Med Chem Lett ; 26(4): 1260-4, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26810316

RESUMO

Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.


Assuntos
Imidazóis/química , Piridinas/química , Piridonas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Imidazóis/sangue , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Locomoção/efeitos dos fármacos , Ligação Proteica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/sangue , Piridonas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade
17.
Neuroimage ; 127: 445-455, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26522425

RESUMO

Cerebral blood volume (CBV) fMRI with ultrasmall superparamagnetic iron oxide particles (USPIO) as a contrast agent was used to investigate olfactory processing in rats. fMRI data were acquired in sixteen 0.75-mm coronal slices covering the olfactory bulb (OB) and higher olfactory regions (HOR), including the anterior olfactory nucleus and piriform cortex. For each animal, multiple consecutive fMRI measurements were made during a 3-h experiment session, with each measurement consisting of a baseline period, an odorant stimulation period, and a recovery period. Two different stimulation paradigms with a stimulation period of 40s or 80s, respectively, were used to study olfactory processing. Odorant-induced CBV increases were robustly observed in the OB and HOR of each individual animal. Olfactory adaptation, which is characterized by an attenuation of responses to continuous exposure or repeated stimulations, has different characteristics in the OB and HOR. For adaptation to repeated stimuli, while it was observed in both the OB and HOR, CBV responses in the HOR were attenuated more significantly than responses in the OB. In contrast, within each continuous 40-s or 80-s odor exposure, CBV responses in the OB were stable and did not show adaptation, but the CBV responses in the HOR were state dependent, with no adaptation during initial exposures, but significant adaptation during following exposures. These results support previous reports that HOR plays a more significant role than OB in olfactory habituation. The technical approach presented in this study should enable more extensive fMRI studies of olfactory processing in rats.


Assuntos
Habituação Psicofisiológica/fisiologia , Bulbo Olfatório/fisiologia , Córtex Olfatório/fisiologia , Percepção Olfatória/fisiologia , Animais , Mapeamento Encefálico , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Condutos Olfatórios/fisiologia , Ratos , Ratos Sprague-Dawley
18.
J Pharmacol Exp Ther ; 355(3): 442-50, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26446308

RESUMO

Improved treatment of Alzheimer disease (AD) is a significant unmet medical need that is becoming even more critical given the rise in the number of patients and the substantial economic burden. The current standards of care, acetylcholinesterase inhibitors (AChEIs), are hindered by gastrointestinal side effects owing to their nonselective activation of muscarinic and nicotinic receptors. Recently, the highly selective M1 positive allosteric modulator PQCA (1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl-4-oxo-4 H-quinolizine-3-carboxylic acid) has been demonstrated to improve cognition in a variety of rodent and nonhuman primate cognition models without producing significant gastrointestinal side effects. Here we describe the effect of PQCA and the AChEI donepezil on two clinically relevant and highly translatable touchscreen cognition tasks in nonhuman primates: paired-associates learning (PAL) and the continuous-performance task (CPT). Blockade of muscarinic signaling by scopolamine produced significant impairments in both PAL and CPT. PQCA and donepezil attenuated the scopolamine deficits in both tasks, and the action of these two compounds was similar in magnitude. In addition, the combination of subeffective doses of PQCA and donepezil enhanced PAL performance. These results further suggest that M1-positive allosteric modulators, either as monotherapy or as an add-on to current standards of care, have potential to reduce the cognitive deficits associated with AD.


Assuntos
Atenção/efeitos dos fármacos , Memória/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Piperidinas/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Quinolizinas/farmacologia , Receptor Muscarínico M1/efeitos dos fármacos , Animais , Aprendizagem por Associação/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Cognição/efeitos dos fármacos , Donepezila , Relação Dose-Resposta a Droga , Indanos/farmacologia , Macaca mulatta , Masculino , Antagonistas Muscarínicos/farmacologia , Escopolamina/farmacologia
19.
J Med Chem ; 58(19): 7888-94, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26378882

RESUMO

Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.


Assuntos
Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade , Animais , Técnicas de Química Sintética , Cristalografia por Raios X , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/química , Ratos Wistar , Esquizofrenia/tratamento farmacológico
20.
Behav Brain Res ; 287: 96-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25800972

RESUMO

We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Aß were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Colinérgicos/farmacologia , Transtornos da Memória/tratamento farmacológico , Nootrópicos/farmacologia , Piperidinas/farmacologia , Quinolizinas/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Doença de Alzheimer/fisiopatologia , Animais , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Donepezila , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Indanos/farmacologia , Transtornos da Memória/fisiopatologia , Camundongos Transgênicos , Receptor Muscarínico M1/metabolismo , /fisiologia
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