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1.
Bioorg Med Chem Lett ; 30(14): 127243, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32527545

RESUMO

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.


Assuntos
Amidas/farmacologia , Azetidinas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Piperazinas/farmacologia , Amidas/química , Azetidinas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Monoacilglicerol Lipases/metabolismo , Piperazinas/química , Relação Estrutura-Atividade
2.
J Pharmacol Exp Ther ; 372(3): 339-353, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31818916

RESUMO

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Monoacilglicerol Lipases/antagonistas & inibidores , Piperazinas/farmacologia , Animais , Ligação Competitiva , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/sangue , Escherichia coli/enzimologia , Escherichia coli/genética , Células HeLa , Humanos , Cinética , Leucócitos Mononucleares/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Monoacilglicerol Lipases/genética , Dor/tratamento farmacológico , Piperazinas/sangue , Ligação Proteica , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Sono REM/efeitos dos fármacos , Especificidade por Substrato
3.
Bioorg Med Chem Lett ; 28(23-24): 3780-3783, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30337231

RESUMO

A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.


Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo N/metabolismo , Neuralgia/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Descoberta de Drogas , Células HEK293 , Humanos , Masculino , Neuralgia/metabolismo , Técnicas de Patch-Clamp , Piranos/química , Piranos/farmacologia , Piranos/uso terapêutico , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley
4.
J Med Chem ; 58(9): 3859-74, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25850459

RESUMO

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.


Assuntos
Analgésicos/química , Benzimidazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Carragenina , Cães , Adjuvante de Freund , Células HEK293 , Haplorrinos , Temperatura Alta , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 23(7): 2234-7, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23411075

RESUMO

A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.


Assuntos
Glicina/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicina/análogos & derivados , Glicina/química , Células HEK293 , Humanos , Estrutura Molecular , Pirimidinonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Canais de Cátion TRPM/agonistas
8.
Bioorg Med Chem Lett ; 22(12): 4080-3, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22608964

RESUMO

Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.


Assuntos
Analgésicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/metabolismo , Dor Crônica/tratamento farmacológico , Neuralgia/tratamento farmacológico , Piperidinas/síntese química , Pirazóis/síntese química , Analgésicos/uso terapêutico , Animais , Bloqueadores dos Canais de Cálcio/uso terapêutico , Linhagem Celular , Dor Crônica/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Neuralgia/metabolismo , Técnicas de Patch-Clamp , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Relação Estrutura-Atividade , ômega-Conotoxinas/uso terapêutico
9.
Bioorg Med Chem Lett ; 22(8): 2922-6, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22421018

RESUMO

A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.


Assuntos
Desenho de Fármacos , Organofosfonatos/síntese química , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cães , Concentração Inibidora 50 , Estrutura Molecular , Organofosfonatos/química , Organofosfonatos/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
10.
Pharmaceuticals (Basel) ; 5(2): 114-32, 2012 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-24288084

RESUMO

In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under certain conditions. The focus of this review is to summarize the current perspectives of TRPV1 for the treatment of conditions beyond those with a primary thermal sensitivity.

11.
Toxicol Sci ; 117(2): 493-504, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20616206

RESUMO

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic ß-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic ß-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.


Assuntos
Ciproeptadina/toxicidade , Hiperglicemia/induzido quimicamente , Células Secretoras de Insulina/efeitos dos fármacos , Antagonistas de Entorpecentes/toxicidade , Pâncreas/efeitos dos fármacos , Antagonistas da Serotonina/toxicidade , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciproeptadina/análogos & derivados , Diabetes Mellitus Tipo 1/metabolismo , Cães , Epífises/anormalidades , Epífises/metabolismo , Feminino , Ensaios de Triagem em Larga Escala , Hiperglicemia/metabolismo , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Insulinoma/tratamento farmacológico , Insulinoma/metabolismo , Masculino , Camundongos , Osteocondrodisplasias/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestrutura
12.
Pharmacol Biochem Behav ; 96(2): 130-5, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20438745

RESUMO

Discovered as part of an effort to identify delta opioid (DOPr or DOR) agonist analgesics, JNJ-20788560 and JNJ-39204880 exhibited high DOR affinity, with K(i) values of 1.7 and 2.0nM, respectively, and were selective for DOR over the mu opioid receptor (MOPr or MOR), with 596- and 122-fold selectivity, respectively. Both compounds stimulated DOR but not MOR induced GTPgammaS binding and were effective antihyperalgesic agents in the complete Freund's adjuvant model of thermal hyperalgesia in the rat, with oral ED(50) values of 13.5 and 35mg/kg, corresponding to plasma levels of 1 and 9microM, respectively. Autoradiographic analysis of DOR and MOR occupancy in sections of brain (striatum) and lumbar spinal cord (L4-L6) was determined ex vivo, using radiolabeled naltrindole or DAMGO. Quantitative image analysis resulted in striatal DOR ED(50) values of 6.9 and 10.7mg/kg, for JNJ-20788560 and JNJ-39204880 respectively, and spinal cord values of 6.4 and 3.2mg/kg, respectively. Neither compound dose-dependently occupied MOR within the dose range studied. Thus, this study confirmed the DOR selectively over MOR of both compounds following their oral administration, and further demonstrated dose-dependent DOR occupancy by each compound across its antihyperalgesic dose range. Importantly, these in vitro, in vivo, and ex vivo data revealed that the greater in vitro potency of JNJ-20788560 was paralleled by its greater in vivo potency, although JNJ-39204880 achieved higher plasma levels following its oral administration. The receptor occupancy levels observed at the pharmacologic ED(50) doses of these compounds suggest the need for greater target engagement by JNJ-39204880 than by JNJ-20788560 to elicit a similar therapeutic response.


Assuntos
Analgésicos Opioides/farmacologia , Autorradiografia/métodos , Compostos Azabicíclicos/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Receptores Opioides delta/agonistas , Xantenos/farmacologia , Analgésicos Opioides/sangue , Animais , Compostos Azabicíclicos/sangue , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/análise , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Vértebras Lombares/diagnóstico por imagem , Masculino , Naltrexona/análogos & derivados , Naltrexona/análise , Medição da Dor/efeitos dos fármacos , Pirimidinas/sangue , Pirrolidinas/sangue , Radiografia , Ensaio Radioligante/métodos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Opioides delta/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Medula Espinal/diagnóstico por imagem , Medula Espinal/metabolismo , Xantenos/sangue
13.
J Med Chem ; 52(3): 771-8, 2009 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-19146418

RESUMO

Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.


Assuntos
Compostos Azabicíclicos/farmacocinética , Organofosfonatos/farmacocinética , Pró-Fármacos/farmacocinética , Administração Oral , Animais , Compostos Azabicíclicos/administração & dosagem , Bile/metabolismo , Disponibilidade Biológica , Difosfonatos/síntese química , Difosfonatos/farmacocinética , Estabilidade de Medicamentos , Suco Gástrico/metabolismo , Masculino , Organofosfonatos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
14.
Bioorg Med Chem Lett ; 18(16): 4569-72, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18662879

RESUMO

A series of piperidine carboxamides were developed as potent antagonists of the transient receptor potential vanilloid-1 (TRPV1), an emerging target for the treatment of pain. A focused library of polar head groups led to the identification of a benzoxazinone amide that afforded good potency in cell-based assays. Synthesis and a QSAR model will be presented.


Assuntos
Amidas/química , Benzoxazinas/farmacologia , Piperidinas/química , Canais de Cátion TRPV/antagonistas & inibidores , Benzoxazinas/química , Capsaicina/química , Proteínas de Transporte/antagonistas & inibidores , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Relação Estrutura-Atividade
15.
16.
Neuropsychopharmacology ; 33(6): 1323-35, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17625499

RESUMO

One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT6 receptor and profile as full receptor agonists (WAY-181187: EC50=6.6 nM, Emax=93%; WAY-208466: EC50=7.3 nM; Emax=100%). In the rat frontal cortex, acute administration of WAY-181187 (3-30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 microM), confirming a local relationship between 5-HT6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10-30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT6 receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT(6) receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56-178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT6 receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD).


Assuntos
Encéfalo/efeitos dos fármacos , Neurofarmacologia , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Aminoácidos/metabolismo , Análise de Variância , Animais , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Interações Medicamentosas , Humanos , Isquemia/induzido quimicamente , Isquemia/tratamento farmacológico , Masculino , Microdiálise/métodos , Cloreto de Potássio , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Azida Sódica
17.
Neuron ; 54(3): 379-86, 2007 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-17481392

RESUMO

Thermosensation is an essential sensory function that is subserved by a variety of transducer molecules, including those from the Transient Receptor Potential (TRP) ion channel superfamily. One of its members, TRPM8 (CMR1), a ligand-gated, nonselective cation channel, is activated by both cold and chemical stimuli in vitro. However, its roles in cold thermosensation and pain in vivo have not been fully elucidated. Here, we show that sensory neurons derived from TRPM8 null mice lack detectable levels of TRPM8 mRNA and protein and that the number of these neurons responding to cold (18 degrees C) and menthol (100 microM) is greatly decreased. Furthermore, compared with WT mice, TRPM8 null mice display deficiencies in certain behaviors, including icilin-induced jumping and cold sensation, as well as a significant reduction in injury-induced responsiveness to acetone cooling. These results suggest that TRPM8 may play an important role in certain types of cold-induced pain in humans.


Assuntos
Temperatura Baixa , Camundongos Knockout/fisiologia , Canais de Cátion TRPM/deficiência , Sensação Térmica/genética , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cálcio/metabolismo , Capsaicina/farmacologia , Células Cultivadas , Gânglios Espinais/citologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/fisiopatologia , Metanol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Medição da Dor/métodos , Pirimidinonas/farmacologia , Tempo de Reação/efeitos dos fármacos
18.
J Pharmacol Exp Ther ; 320(3): 1178-85, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17142646

RESUMO

There is increasing recognition that norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors (NRIs and SRIs) are efficacious in treating some types of pain. To date, studies have not systematically evaluated the relative activity at the NE and/or 5-HT transporter required for maximal efficacy in rodent pain models. Known selective NE and 5-HT reuptake inhibitors reboxetine, desipramine, fluoxetine, and paroxetine were evaluated in both in vitro and in vivo assays. Using the spinal nerve ligation model of neuropathic pain, the compounds differentially reversed tactile allodynia. Evaluation of a broader spectrum of reuptake inhibitors in the para-phenylquinone (PPQ)-induced abdominal constriction model, a model of acute visceral pain, demonstrated that both the SRIs and the NRIs significantly blocked abdominal constrictions. However, the magnitude of this effect was greater following treatment with compounds having greater affinity for NRI compared with SRI affinity. In addition, isobolographic analyses indicated significant synergistic effects for all combinations of desipramine and fluoxetine in the PPQ model of visceral pain. Collectively, the present results support the hypothesis that compounds with greater NRI activity should be more effective for the treatment of pain than compounds having only SRI activity, and this hypothesis is also supported by clinical data. These studies also suggest that the potency and effectiveness of NRIs might be enhanced by the presence of 5-HT activity.


Assuntos
Analgésicos não Narcóticos/uso terapêutico , Norepinefrina/uso terapêutico , Dor/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Norepinefrina/administração & dosagem , Norepinefrina/farmacologia , Dor/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fatores de Tempo
19.
Eur J Pharmacol ; 553(1-3): 146-8, 2006 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-17056036

RESUMO

ERB-041 (2-(3-Fluoro-4-hydroxyphenyl)-7-vinyl-1,3 benzoxazol-5-ol) is a selective estrogen receptor-beta agonist with activity in rodent models of rheumatoid arthritis and endometriosis. Clinical trials for these diseases are underway: however, the role of estrogen receptor-beta in modulating pain associated with inflammation remains unknown. These studies demonstrate that acutely administered ERB-041 is anti-hyperalgesic in preclinical models of chemical-induced and acute inflammatory pain, thus suggesting that ERB-041 may be useful for modulating pain associated with some types of inflammation.


Assuntos
Receptor beta de Estrogênio/agonistas , Inflamação/induzido quimicamente , Oxazóis/farmacologia , Dor/induzido quimicamente , Animais , Relação Dose-Resposta a Droga , Estradiol/análogos & derivados , Estradiol/farmacologia , Fulvestranto , Temperatura Alta , Hiperalgesia/tratamento farmacológico , Inflamação/complicações , Masculino , Dor/etiologia , Ratos , Ratos Sprague-Dawley
20.
Brain Res ; 1095(1): 65-72, 2006 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-16730668

RESUMO

A greater knowledge of the neurochemical changes occurring during pain states will undoubtedly aid in the discovery of effective pain pharmacotherapies. This study highlights the acute effects of inflammatory agents on neurochemical changes in the rostral ventromedial medulla (RVM), a supraspinal site involved in the processing of painful stimuli. Consistent with previous reports, a peripheral injection of 0.1 mg prostaglandin E(2) (PGE(2)) into the intraplantar area of the rat paw produced thermal hypersensitivity that peaked 10 min after administration. In vivo microdialysis studies in the same animals revealed that this behavioral response correlated with a greater than 2-fold increase (230%) in extracellular serotonin (5-HT) levels in the RVM. In contrast, levels of other neurotransmitters measured, including norepinephrine and dopamine, were not altered in animals receiving this inflammatory agent. Similar to PGE(2), an intraplantar injection of capsaicin (0.1 mg) produced a robust thermal hypersensitivity that was paralleled by a 3-fold increase in levels of 5-HT in the RVM. The next series of experiments showed that acute administration of the opioid analgesic, morphine (5.6 mg/kg; IP), attenuated PGE(2)-induced thermal hypersensitivity and reversed the increase in extracellular 5-HT observed in the RVM. Taken together, these findings extend previous reports of central neurochemical changes during inflammatory pain conditions and show that the combination of behavioral endpoints with microdialysis can yield important insights into the neurochemical environment of the pain circuitry.


Assuntos
Química Encefálica/fisiologia , Bulbo/metabolismo , Dor/etiologia , Dor/metabolismo , Análise de Variância , Animais , Comportamento Animal , Monoaminas Biogênicas/metabolismo , Química Encefálica/efeitos dos fármacos , Capsaicina/efeitos adversos , Cromatografia Líquida de Alta Pressão/métodos , Dinoprostona/efeitos adversos , Interações Medicamentosas , Eletroquímica/métodos , Temperatura Alta/efeitos adversos , Masculino , Bulbo/efeitos dos fármacos , Microdiálise/métodos , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Dor/tratamento farmacológico , Dor/patologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Tempo de Reação/efeitos da radiação
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