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1.
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.

2.
Phys Ther ; 98(5): 424-433, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29669085

RESUMO

The implementation of recent Centers for Disease Control and Prevention recommendations to move away from opioids and toward nonpharmacological therapies for the treatment of chronic pain could involve a difficult transition period for patients and practitioners. The focus of treatment should shift from eliminating pain completely to minimizing the impact of pain on quality of life. Many patients with chronic pain take opioids either because opioids were previously prescribed as a first-line treatment for chronic pain, on the basis of old standards of care, or because opioids were initially prescribed for acute pain. Patients currently taking opioids will need a tapering period during which they transition their pain management to interdisciplinary care and nonpharmacological treatments. To provide useful treatment options, physical therapists need to have a good understanding of the neuroscientific mechanisms of chronic pain, biopsychosocial components of chronic pain management, issues related to opioid use, and pain management strategies used by other health care professionals. Armed with knowledge and good communication skills, physical therapists can work within an interdisciplinary team to adapt care to each patient's needs and abilities. This perspective article provides guidance for physical therapists to effectively treat patients with chronic pain during the opioid tapering process. A framework has been created to help health care providers structure their reasoning as they collaborate to develop a unique approach for each patient.


Assuntos
Analgésicos Opioides/administração & dosagem , Dor Crônica/psicologia , Dor Crônica/terapia , Manejo da Dor/métodos , Modalidades de Fisioterapia , Tomada de Decisões , Humanos , Qualidade de Vida
3.
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
4.
Biol Psychiatry ; 68(8): 712-8, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20579972

RESUMO

BACKGROUND: Recent evidence suggests an involvement of T-type calcium channels in the effects of drugs of abuse. METHODS: We examined the influence of the novel, potent, and selective T-type calcium channel antagonist [2-(4-cyclopropylphenyl)-N-((1R)-1-{5-[2,2,2-trifluoroethyl]oxo}pyridine-2-yl)ethyl]acetamide] (TTA-A2) (.3, 1, or 3 mg/kg) on motivation for nicotine, as measured by nicotine self-administration on a progressive ratio (PR) schedule, and nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine delivery (n = 11 or 12 Long Evans rats/group). Furthermore, we examined the specificity of the TTA-A2 effects by characterizing its influence on PR responding for food (in the absence or presence of nicotine-potentiated responding), food- versus nicotine-induced cue-potentiated reinstatement for a response previously reinforced by food administration (n = 11 or 12 Wistar Hannover rats/group), and its ability to induce a conditioned place aversion. RESULTS: TTA-A2 dose-dependently decreased self-administration of nicotine on a PR schedule and the ability of both nicotine and a cue paired with nicotine to reinstate responding. The effects were specific for nicotine's incentive motivational properties, as TTA-A2 did not influence responding for food on a PR schedule but did attenuate the ability of nicotine to potentiate responding for food. Likewise, TTA-A2 did not alter food-induced cue-potentiated reinstatement for a response previously reinforced by food but did decrease nicotine-induced cue-potentiated reinstatement. Finally, TTA-A2 did not produce an aversive state, as indicated by a lack of ability to induce conditioned place aversion. CONCLUSIONS: These data suggest that T-type calcium channel antagonists have potential for alleviating nicotine addiction by selectively decreasing the incentive motivational properties of nicotine.


Assuntos
Benzenoacetamidas/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Motivação/efeitos dos fármacos , Nicotina/farmacologia , Piridinas/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Relação Dose-Resposta a Droga , Alimentos , Masculino , Nicotina/administração & dosagem , Nicotina/antagonistas & inibidores , Ratos , Ratos Long-Evans , Ratos Wistar , Esquema de Reforço , Autoadministração
5.
Eur J Pharmacol ; 634(1-3): 95-100, 2010 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-20223232

RESUMO

Etazolate is a phosphodiesterase 4 (PDE4) inhibitor and GABAA receptor modulator that also stimulates alpha-secretase activity and neurotrophic soluble amyloid precursor protein (sAPPalpha) production, currently developed as a possible Alzheimer's disease therapeutic. In this study two doses of etazolate were tested for cognitive effects in normally aged rats, using a complex spatial learning and memory task that emphasized two naturally occurring behaviors in rodents, foraging for food and returning large pieces of found food to a safe home location. Both etazolate doses completely prevented both (1) a foraging deficit that developed in untreated aged rats over the course of the test, as well as (2) a trial-specific deficit in memory for previously visited food locations that also developed over the course of the test in untreated aged rats. Both doses also significantly reduced a separate memory deficit for changing locations of the animals' home box, plus completely prevented a significant tendency for untreated aged animals to attempt entry into similar-appearing but incorrect home boxes. The combined behavioral data demonstrate positive effects of etazolate on separate age-related cognitive deficits, using a complex task based on naturally occurring rodent behaviors.


Assuntos
Envelhecimento/efeitos dos fármacos , Etazolato/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento de Retorno ao Território Vital/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Envelhecimento/fisiologia , Envelhecimento/psicologia , Animais , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Etazolato/uso terapêutico , Comportamento Alimentar/fisiologia , Comportamento Alimentar/psicologia , Comportamento de Retorno ao Território Vital/fisiologia , Masculino , Desempenho Psicomotor/fisiologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344
6.
Behav Brain Res ; 207(1): 37-43, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-19799936

RESUMO

RATIONALE: Compounds which decrease NMDA receptor functioning, such as PCP and ketamine have abuse liability, whereas co-agonists of the NMDA receptor attenuate some of the behavioral and neurochemical effects of stimulant drugs. Here we examined the effects of a glycine transporter (GlyT1) inhibitor, which elevates glycine and hence NMDA signaling, on the behavioral effects of nicotine. OBJECTIVES: To examine the influence of a novel potent, selective, and brain penetrant GlyT1 inhibitor, compound 5 {(2-chloro-N-[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methyl)}-4-(trifluoromethyl)benzamide; human IC(50)=22 nM; rat=30 nM), on nicotine-induced potentiation of progressive ratio responding for a food reward and nicotine- and food-induced cue-potentiated reinstatement for a response previously paired with sucrose. RESULTS: Compound 5 (33 mg/kg; p.o.; achieving approximately 62% GlyT1 blockade) significantly attenuated nicotine-, but not food-induced cue-potentiated reinstatement for a response previously paired with sucrose whereas a lower dose (11 mg/kg, which achieved approximately 34% GlyT1 blockade) did not. The effect of the higher dose was similar to that observed for mecamylamine (1mg/kg i.p.), a non-selective nicotinic receptor antagonist. CONCLUSIONS: These results suggest that compound 5 influences the ability of nicotine to promote reinstatement in the presence of a cue embedded with incentive motivation. Given the hypothesized contribution of reinstatement and conditioned stimuli to drug abuse and relapse, these findings suggest that GlyT1 inhibitors could have utility for treating nicotine addiction.


Assuntos
Benzamidas/farmacologia , Alimentos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Nicotina/administração & dosagem , Piperidinas/farmacologia , Análise de Variância , Animais , Comportamento Aditivo , Comportamento Animal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Masculino , Mecamilamina/farmacologia , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Wistar , Receptores Nicotínicos/metabolismo , Esquema de Reforço , Autoadministração , Sacarose/administração & dosagem
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