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1.
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.

2.
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.

3.
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.

4.
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
5.
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
6.
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
7.
Dev Neurobiol ; 70(2): 73-86, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19885833

RESUMO

Sex steroids facilitate dramatic changes in behavioral responses to sociosexual signals and are increasingly implicated in the sensory processing of those signals. Our previous work demonstrated that in female white-throated sparrows, which are seasonal breeders, genomic responses in the auditory forebrain are selective for conspecific song over frequency-matched tones only when plasma estradiol (E2) reaches breeding levels. Here, we sought to map this E2-dependent selectivity in the best-studied area of the auditory forebrain, the caudomedial nidopallium (NCM). Nonbreeding females with low endogenous levels of E2 were treated with E2 or a placebo and exposed to conspecific song, tones, or no sound playback. Immunoreactive protein product of the immediate early gene zenk (egr-1) was then quantified within seven distinct subregions, or domains, of NCM. We report three main findings: (1) regardless of hormone treatment, the zenk response is significantly higher in dorsal than in ventral NCM, and higher in medial than in lateral NCM; (2) E2-dependent selectivity of the response is limited to the rostral and medial domains of NCM; in the more caudal domains, song induces more zenk expression than tones regardless of hormone treatment; (3) even when no sound stimuli were presented, E2 treatment significantly increased zenk expression in the rostral, but not the caudal, domains of NCM. Together, the latter two findings suggest that E2-dependent plasticity in NCM is concentrated in rostral NCM, which is hodologically and neurochemically distinct from caudal NCM. Activity in rostral NCM may therefore be seasonally regulated in this species.


Assuntos
Percepção Auditiva/fisiologia , Proteínas Aviárias/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Estradiol/metabolismo , Prosencéfalo/fisiologia , Vocalização Animal , Estimulação Acústica , Análise de Variância , Animais , Vias Auditivas/fisiologia , Proteínas Aviárias/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Estradiol/sangue , Feminino , Regulação da Expressão Gênica/fisiologia , Radioimunoensaio , Distribuição Aleatória , Pardais
8.
Horm Behav ; 55(1): 113-20, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18848562

RESUMO

White-throated sparrows (Zonotrichia albicollis) exhibit a behavioral polymorphism that segregates with a plumage marker. Individuals with a white stripe (WS) on the crown engage in an aggressive strategy that involves more singing, whereas individuals with a tan stripe (TS) sing less and engage in more parental care. Previous work has shown that plasma levels of gonadal steroids differ between the morphs in both sexes, suggesting a hormonal mechanism for the polymorphic behavior in this species. Here, we eliminated morph differences in plasma levels of testosterone (T) in males and estradiol (E2) in females in order to test whether morph differences in behavior would be similarly eliminated. Males and females in non-breeding condition were treated with T or E2, respectively, so that plasma levels in the treated groups were high and equal between the WS and TS morphs. We found that despite hormone treatment, WS and TS birds differed with respect to singing behavior. WS males sang more in response to song playback than did TS males, and WS females exhibited more spontaneous song than TS females. We also found that WS males gave more chip calls, which are often used in contexts of territorial aggression. Overall, these results suggest that WS birds engage in more territorial vocalization, particularly song, than do TS birds, even when T or E2 levels are experimentally equalized. This behavioral difference may therefore be driven by other factors, such as steroid metabolism, receptor expression or function, or steroid-independent neurotransmitter systems.


Assuntos
Estradiol/farmacologia , Testosterona/farmacologia , Vocalização Animal/efeitos dos fármacos , Estimulação Acústica , Agressão/efeitos dos fármacos , Análise de Variância , Animais , Estradiol/sangue , Feminino , Masculino , Fenótipo , Radioimunoensaio , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Social , Pardais , Testosterona/sangue
9.
J Comp Neurol ; 511(2): 173-86, 2008 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-18770869

RESUMO

Social behaviors such as courtship, parenting, and aggression depend primarily on two factors: a social signal to trigger the behavior, and a hormonal milieu that facilitates or permits it. Gonadal steroids may alter the valence or perceived context of the signal so that the same pheromone, vocalization, or visual display may elicit very different responses depending on the receiver's plasma hormone level. The neural processes underlying this phenomenon, however, are not well understood. Here, we describe how hormones modulate neural responses to social signals in female white-throated sparrows listening to recordings of male song. While manipulating levels of the ovarian steroid estradiol, we mapped and quantified sound-induced expression of the immediate early gene egr-1 in nine brain regions that constitute a social behavior network in vertebrates. In most regions of interest, hearing male song induced more expression than hearing tones or silence, and this selectivity for song was seen only in birds with estradiol levels typical of the breeding season. In females with regressed ovaries and no exogenous estradiol, neural responses were selective for song over tones only in the lateral portion of the ventromedial hypothalamus, not in the rest of the network. Because the effects of hormone treatment on neural responses are not identical in each region, the overall pattern of activation across the network changes with estradiol level and thus with season and breeding context. Our results demonstrate a possible mechanism by which gonadal steroids may alter the processing of social signals and affect social decision-making.


Assuntos
Estradiol/sangue , Neurônios/metabolismo , Comportamento Social , Pardais , Vocalização Animal/fisiologia , Animais , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Luz , Masculino , Rede Nervosa/anatomia & histologia , Rede Nervosa/fisiologia , Fotoperíodo , Pardais/anatomia & histologia , Pardais/fisiologia
10.
Gen Comp Endocrinol ; 156(2): 426-33, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18275963

RESUMO

The white-throated sparrow (Zonotrichia albicollis) lends itself particularly well to investigations of neuroendocrine mechanisms of social behavior because of a behavioral polymorphism that correlates with a plumage phenotype. Roughly half of the individuals of this species exhibit a white stripe (WS) on the crown and engage in a more aggressive strategy, whereas the other half exhibit a tan stripe (TS) and assume a more parental strategy. These behavioral differences are mirrored by hormonal and neuroendocrine differences; for example, males of the WS morph have higher plasma testosterone than do TS males, and females of the TS morph have higher plasma luteinizing hormone than females of the WS morph. These differences suggest that the regulation of the hypothalamic-pituitary-gonadal (HPG) axis may differ according to morph. In this study, we compared HPG axis activity at each level by measuring (1) the number, size, and staining intensity of GnRH immunoreactive (ir) neurons; (2) plasma LH; and (3) plasma estradiol (E2) in females. We found that TS females had more GnRH-ir neurons in the septo-preoptic area of the hypothalamus than did WS females, and GnRH-ir neuronal cell bodies were larger in the WS than the TS females. There was no morph difference in the intensity of GnRH labeling. TS females had higher plasma LH, which is consistent with a previous report, and higher plasma E2. We hypothesize that the differences in GnRH-ir cell number and size are related to differences in LH and E2 secretion, and may be relevant to polymorphic social behavior.


Assuntos
Comportamento Animal/fisiologia , Gônadas/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Pardais/fisiologia , Animais , Contagem de Células , Cor , Estradiol/sangue , Feminino , Hormônio Liberador de Gonadotropina/fisiologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Hormônio Luteinizante/sangue , Ovário/crescimento & desenvolvimento , Fenótipo , Estimulação Luminosa , Reprodução/fisiologia
11.
Endocrinology ; 148(12): 5614-23, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17823268

RESUMO

In many species, courtship signals enhance reproductive function in the receiver. How these social signals are processed by the brain, particularly how they induce an endocrine response, is not well understood. Songbirds provide an ideal model in which to study this phenomenon because of the large existing literature on both their auditory neurobiology and the control of their reproductive physiology by environmental cues. To date, all of the relevant studies on songbirds have involved measuring the effects of male vocalizations on ovarian function over a period of weeks, a time course that precludes detailed analysis of the neuroendocrine mechanisms operating during song perception. We played recordings of conspecific male song to laboratory-housed female white-throated sparrows and quantified the resulting rapid changes in LH as well as the induction of the immediate early gene Egr-1 in the GnRH system and mediobasal hypothalamus (MBH). Hearing song for 42 min induced LH release and Egr-1 expression in the MBH, but did not alter Egr-1 expression in GnRH neurons. The time course of LH release and the pattern of Egr-1 expression together suggest that song acts as a trigger to induce GnRH release in a manner resembling photostimulation. The Egr-1 response in the MBH was qualitatively distinguishable from the responses to either photostimulation or pharmacologically induced LH release but seemed to involve overlapping neuronal populations. Song-induced Egr-1 expression in the MBH was correlated with the expression in midbrain and forebrain auditory centers, further supporting a role for the MBH in processing social information.


Assuntos
Corte , Sistemas Neurossecretores/metabolismo , Pardais/fisiologia , Vocalização Animal/fisiologia , Animais , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Imuno-Histoquímica , Hormônio Luteinizante/metabolismo , Masculino , Modelos Biológicos , Sistemas Neurossecretores/fisiologia , Fotoperíodo
12.
Anim Cogn ; 10(2): 105-15, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16909232

RESUMO

Fluctuations of ovarian hormones across the menstrual cycle influence a variety of social and cognitive behaviors in primates. For example, female rhesus monkeys exhibit heightened interest for males and increased agonistic interactions with other females during periods of high estrogen levels. In the present study, we hypothesized that females' preference for males during periods of high estrogen levels is also expressed at the level of face perception. We tested four intact females on two face-tasks involving neutral portraits of male and female rhesus monkeys, chimpanzees and humans. In the visual preference task (VP), monkeys had to touch a button to view a face image. The image remained on the screen as long as the button was touched, and the duration of pressing was taken as an index of the monkey's looking time for the face stimulus. In the Face-Delayed Recognition Span Test (Face-DRST), monkeys were rewarded for touching the new face in an increasing number of serially presented faces. Monkeys were tested 5 days a week across one menstrual cycle. Blood was collected every other day for analysis of estradiol and progesterone. Two of the four females were cycling at the time of testing. We did not find an influence of the cycle on Face-DRST, likely due to a floor effect. In the VP however, the two cycling individuals looked longer at conspecific male faces than female faces during the peri-ovulatory period of the cycle. Such effects were absent for human and chimpanzee faces and for the two noncycling subjects. These data suggest that ovarian hormones may influence females' preferences for specific faces, with heightened preference for male faces during the peri-ovulatory period of the cycle. Heightened interest for stimuli of significant reproductive relevance during periods of high conception risk may help guide social and sexual behavior in the rhesus monkey.


Assuntos
Comportamento Animal , Face , Macaca mulatta/fisiologia , Ciclo Menstrual/fisiologia , Reconhecimento Visual de Modelos , Animais , Aprendizagem por Discriminação , Estradiol/sangue , Feminino , Humanos , Masculino , Ciclo Menstrual/sangue
13.
Horm Behav ; 50(2): 274-84, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16678823

RESUMO

Click-evoked otoacoustic emissions (CEOAEs) and distortion-product OAEs (DPOAEs) were measured in about 60 rhesus monkeys. CEOAE strength was substantially greater in females than in males, just as in humans. DPOAE strength was generally slightly stronger in females, just as in humans. In males, CEOAEs were weaker (more masculine) in the fall breeding season and in winter than in the summer. In females, CEOAEs were slightly stronger (more feminine) in the fall, when sex steroids are elevated in females (and males), than in the summer when rhesus monkeys are reproductively quiescent. Thus, the sex differences in CEOAEs were greater in the fall than in the summer. We presume that the seasonal fluctuations in OAEs reflect activational hormonal effects, while the basic sex differences in OAEs likely reflect organizational effects of prenatal androgen exposure. Some monkeys of both sexes had been treated with additional testosterone or the anti-androgen flutamide during prenatal development. In accord with expectations, prenatal androgen treatment weakened CEOAEs in females, and prenatal flutamide treatment strengthened CEOAEs in males. For DPOAEs, the differences between treated and untreated groups were mostly small and often inconsistent. Taken as a whole, the data from both rhesus monkeys and humans suggest that the linear, reflection-based mechanism of OAE production that underlies CEOAEs is more sensitive to prenatal androgenic processes than is the nonlinear distortion mechanism that underlies DPOAEs.


Assuntos
Vocalização Animal/fisiologia , Antagonistas de Androgênios/farmacologia , Androgênios/farmacologia , Comunicação Animal , Animais , Cóclea/fisiologia , Interpretação Estatística de Dados , Feminino , Flutamida/farmacologia , Macaca mulatta , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Reprodutibilidade dos Testes , Estações do Ano , Caracteres Sexuais , Testosterona/farmacologia
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