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1.
J Pain ; 9(2): 146-56, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18088559

RESUMO

UNLABELLED: A visceral pain model incorporating use of cyclophosphamide (CP) to induce bladder inflammation has been described. CP treatment in rats produces changes in behavior (abnormal postures and eye closure) and respiration rate indicative of visceral pain. We characterized the dose-dependency and progression of CP-induced cystitis pain after intraperitoneal (i.p.) CP. The behavioral and respiration rate changes were ameliorated by systemic morphine and ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], a neuronal nicotinic acetylcholine receptor agonist, in a manner reversible by naloxone and mecamylamine, respectively. Sites of antinociceptive actions of morphine and ABT-594 were investigated using systemic, intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of blood-brain barrier impenetrant antagonists. Naloxone methiodide produced a complete antagonism of morphine antinociception after i.c.v. but not i.p. or i.t. administration. Chlorisondamine blocked ABT-594 antinociception after i.c.v. but not i.p. administration. Further pharmacological characterization of behavioral and respiration changes in CP-cystitis was performed using standard analgesics. The alpha(2)-adrenoceptor agonist clonidine produced a weak attenuation of CP-pain behavior. NSAIDs (ibuprofen, acetaminophen, and celecoxib) and anticonvulsants (gabapentin and lamotrigine) were without effect. These results demonstrate that morphine and ABT-594 produce antinociception in CP-cystitis by a predominantly supraspinal site of action, and that mechanisms producing robust centrally-mediated antinociception could be beneficial in cystitis pain. PERSPECTIVE: In this article, potential antinociceptive effects of a variety of pharmacological agents were evaluated in a rat cystitis pain model. Morphine and a nicotinic acetylcholine receptor agonist ABT-594 were found to exert potent antinociception in this model. Findings presented here aid identification of agents to treat cystitis pain in the clinic.


Assuntos
Analgésicos/farmacologia , Azetidinas/farmacologia , Morfina/farmacologia , Dor/tratamento farmacológico , Dor/fisiopatologia , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Clorisondamina/administração & dosagem , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/fisiopatologia , Modelos Animais de Doenças , Masculino , Mecamilamina/administração & dosagem , Naloxona/administração & dosagem , Naloxona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas Nicotínicos/administração & dosagem , Compostos de Amônio Quaternário/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/metabolismo , Vísceras/efeitos dos fármacos
2.
J Med Chem ; 50(15): 3651-60, 2007 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-17583335

RESUMO

The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.


Assuntos
Analgésicos/síntese química , Indazóis/síntese química , Compostos de Fenilureia/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Cães , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Indazóis/farmacocinética , Indazóis/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Microssomos Hepáticos/metabolismo , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Ratos , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinética , Ureia/farmacologia
3.
Pain ; 114(1-2): 195-202, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15733645

RESUMO

Metabotropic glutamate receptors (mGluRs) have previously been shown to play a role in pain transmission during inflammatory or neuropathic pain states. However, the role of mGluR5 in post-operative pain remains to be fully investigated. The present study was conducted to characterize analgesic activity of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in the skin-incision-induced post-operative pain model in rats. MPEP is a potent and selective mGluR5 antagonist with high affinity (K(i)=6.3+/-0.9 nM) in rat cortex using [(3)H]-MPEP as a radioligand, while not competing with the mGluR1-selective radioligand [(3)H]-R214127 (K(i)>10,000 nM) in rat cerebellum. Post-operative pain was examined 2 h following surgery using weight-bearing (WB) difference between injured and uninjured paws as a measure of non-evoked pain. In this model, MPEP, as morphine, showed dose-dependent effects and full efficacy after systemic administration (ED(50)=15 mg/kg, i.p. for MPEP, ED(50)=1.3 mg/kg, s.c. for morphine). In addition, intrathecal (i.t.) and intracerebroventricular (i.c.v.) MPEP reduced WB difference (ED(50)=65 microg/rat i.t. and ED(50)=200 microg/rat i.c.v.). Interestingly, intraplantar (i.pl.) injection of MPEP either before or after surgery induced a similar reduction in WB difference (ED(50)=90 microg/rat, i.pl.) while contralateral i.pl. MPEP injection did not produce any effect. These results demonstrate that both peripheral and central mGluR5 receptors play a role in nociceptive transmission observed during post-operative pain. In addition, the data suggest that mGluR5 antagonists could offer a new therapeutic approach to the treatment of post-operative pain.


Assuntos
Dor Pós-Operatória/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Relação Dose-Resposta a Droga , Masculino , Morfina/farmacologia , Morfina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Piridinas/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inibidores
4.
Pain ; 96(1-2): 107-18, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11932067

RESUMO

Adenosine (ADO) is an inhibitory neuromodulator that can increase nociceptive thresholds in response to noxious stimulation. Inhibition of the ADO-metabolizing enzyme, adenosine kinase (AK) increases extracellular ADO concentrations at sites of tissue trauma and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. N7-((1'R,2'S,3'R,4'S)-2',3'-dihydroxy-4'-amino-cyclopentyl)-4-amino-5-bromo-pyrrolo[2,3-a]pyrimidine (A-286501) is a novel and potent (IC50=0.47 nM) carbocyclic nucleoside AK inhibitor that has no significant activity (IC50 >100 microM) at other sites of ADO interaction (A1, A2A, A3 receptors, ADO transporter, and ADO deaminase) or other (IC50 value >10 microM) neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter reuptake sites and enzymes, including cyclooxygenases-1 and -2. A-286501 showed equivalent potency to inhibit AK from several mammalian species and kinetic studies revealed that A-286501 was a reversible and competitive inhibitor with respect to ADO and non-competitive with respect to MgATP2-. A-286501 was orally effective to reduce nociception in animal models of acute (thermal), inflammatory (formalin and carrageenan), and neuropathic (L5/L6 nerve ligation and streptozotocin-induced diabetic) pain. A-286501 was particularly potent (ED50=1 micromol/kg, p.o.) to reduce carrageenan-induced inflammatory thermal hyperalgesia as compared to its analgesic actions in other pain models (acute and neuropathic) and its ability to alter hemodynamic function and motor performance. A-286501 was also effective to reduce carrageenan-induced paw edema and myeloperoxidase activity, a measure of neutrophil influx (ED50=10 micromol/kg, p.o.), in the injured paw. The anti-nociceptive effects of A-286501 in the L5/L6 nerve injury model of neuropathic pain (ED50=20 micromol/kg, p.o.) were not blocked by the opioid antagonist naloxone, but were blocked by the ADO receptor antagonist, theophylline. Following repeated administration, A-286501 showed less potential to produce tolerance as compared to morphine. Thus, A-286501 is a structurally novel AK inhibitor that effectively attenuates nociception by a non-opioid, non-non-steroidal anti-inflammatory drug ADO, receptor mediated mechanism.


Assuntos
Adenosina Quinase/antagonistas & inibidores , Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Hiperalgesia/tratamento farmacológico , Pirimidinas/farmacologia , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ácido Gástrico , Frequência Cardíaca/efeitos dos fármacos , Injeções Intraperitoneais , Atividade Motora/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Nociceptores/efeitos dos fármacos , Pirimidinas/química , Ratos
5.
J Med Chem ; 45(17): 3639-48, 2002 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12166937

RESUMO

Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.


Assuntos
Adenosina Quinase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Morfolinas/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Adenosina/metabolismo , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Morfolinas/química , Morfolinas/farmacologia , Medição da Dor , Fosforilação , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
J Med Chem ; 46(24): 5249-57, 2003 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-14613327

RESUMO

The synthesis and structure-activity relationship of a series of 5,6,7-trisubstituted 4-aminopyrido[2,3-d]pyrimidines as novel nonnucleoside adenosine kinase inhibitors is described. A variety of alkyl, aryl, and heteroaryl substituents were found to be tolerated at the C5, C6, and C7 positions of the pyridopyrimidine core. These studies have led to the identification of analogues that are potent inhibitors of adenosine kinase with in vivo analgesic activity.


Assuntos
Adenosina Quinase/antagonistas & inibidores , Analgésicos/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Adenosina Quinase/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Medição da Dor , Fosforilação , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade
7.
Pharmacol Biochem Behav ; 73(3): 573-81, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12151032

RESUMO

Inhibitors of adenosine kinase (AK) enhance extracellular concentrations of the inhibitory neuromodulator adenosine (ADO) at sites of tissue hyperexcitability and produce antinociceptive effects in animal models of pain and inflammation. The present study compared the ability of several novel and selective AK inhibitors and ADO receptor-selective agonists to attenuate carrageenan-induced thermal hyperalgesia and to impair motor performance as measured by effects on exploratory motor activity and rotorod performance. The prototypical nucleoside AK inhibitor, 5'deoxy-5-iodotubercidin (5'd-5IT), dose-dependently blocked thermal hyperalgesia (ED(50)=0.2 micromol/kg ip) and was 4- and 75-fold less potent in reducing exploratory motor activity and rotorod performance, respectively. The antihyperalgesic effects of 5'd-5IT were fully blocked by the A(1) antagonist, cyclopentyltheophylline (CPT) and the A(2A) antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX). Novel nucleoside and non-nucleoside AK inhibitors (A-134974, A-286501 and ABT-702) also potently (ED(50)=0.7-2 micromol/kg ip) blocked carrageenan-induced thermal hyperalgesia and were significantly less potent than 5'd-5IT in impairing motor performance. The systemic administration of N(6)-cyclopentyladenosine (CPA), an A(1) receptor-selective agonist, CGS 21680, an A(2A) receptor-selective agonist, and N(6)-ethylcarboxamidoadenosine (NECA), a nonselective ADO receptor agonist potently reduced (ED(50)=0.3-1.0 micromol/kg ip) thermal hyperalgesia. Unlike the AK inhibitors, however, these ADO receptor agonists produced significant antinociception only at doses that also decreased motor performance. These data demonstrate that AK inhibitors produce specific antihyperalgesic effects via an interaction with ADO A(1) and A(2A) receptors at doses that lack detectable effects on exploratory motor activity and rotorod performance and offer an improved separation between antinociceptive and motor impairing effects as compared to ADO receptor agonists.


Assuntos
Adenosina Quinase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hiperalgesia/tratamento farmacológico , Desempenho Psicomotor/efeitos dos fármacos , Agonistas do Receptor Purinérgico P1 , Adenosina Quinase/metabolismo , Animais , Carragenina , Relação Dose-Resposta a Droga , Temperatura Alta , Hiperalgesia/induzido quimicamente , Masculino , Atividade Motora/efeitos dos fármacos , Fosforilação , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
8.
Biochem Pharmacol ; 82(8): 967-76, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21620806

RESUMO

Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4ß2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 µmol/kg, i.p.) induced a 6-fold leftward shift of the dose-response of ABT-594 (ED(50)=26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED(50)=26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED(50)=1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose-response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 µmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4ß2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4ß2 nAChR by PAM may represent a novel analgesic approach.


Assuntos
Analgésicos/uso terapêutico , Azetidinas/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Oxidiazóis/uso terapêutico , Dor/tratamento farmacológico , Piridinas/uso terapêutico , Receptores Nicotínicos/metabolismo , Regulação Alostérica , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Animais , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Imageamento por Ressonância Magnética , Masculino , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/efeitos adversos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Oxidiazóis/administração & dosagem , Oxidiazóis/efeitos adversos , Dor/metabolismo , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Ratos , Ratos Sprague-Dawley
9.
Pain ; 152(5): 1165-1172, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21402443

RESUMO

Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Canais de Cálcio/metabolismo , Temperatura Baixa/efeitos adversos , Hiperalgesia/tratamento farmacológico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Dor/fisiopatologia , Sensação/fisiologia , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Regulação da Temperatura Corporal/genética , Regulação da Temperatura Corporal/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Cálcio/metabolismo , Canais de Cálcio/genética , Células Cultivadas , Modelos Animais de Doenças , Interações Medicamentosas , Gânglios Espinais/patologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Hiperalgesia/fisiopatologia , Concentração Inibidora 50 , Isotiocianatos/farmacologia , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Oximas/farmacologia , Oximas/uso terapêutico , Dor/tratamento farmacológico , Dor/genética , Dor/metabolismo , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Sensação/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Canal de Cátion TRPA1 , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Canais de Potencial de Receptor Transitório/genética , Trítio
10.
Pharmacol Biochem Behav ; 95(1): 41-50, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20004681

RESUMO

The histamine H(4) receptor (H(4)R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H(4)R in pain transmission, the effects of JNJ7777120, a potent and selective H(4) antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED(50)=17 mg/kg s.c., 95% CI=8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED(50)=22 mg/kg i.p., 95% CI=10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H(1)R antagonist diphenhydramine, H(2)R antagonists ranitidine, or H(3)R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED(50) of 29 mg/kg i.p. (95% CI=19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED(50)=60 mg/kg) and sciatic nerve constriction injury (ED(50)=88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED(50)=68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H(4) receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.


Assuntos
Analgésicos/farmacologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Analgésicos/uso terapêutico , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ensaio Radioligante , Ratos , Receptores Histamínicos , Receptores Histamínicos H4
11.
Bioorg Med Chem Lett ; 17(14): 3894-9, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17507218

RESUMO

SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.


Assuntos
Analgésicos/farmacologia , Inflamação/tratamento farmacológico , Modelos Biológicos , Dor/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/farmacologia , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Metilação , Ratos , Ureia/farmacocinética , Ureia/uso terapêutico
12.
J Pharmacol Exp Ther ; 319(3): 1376-85, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16982702

RESUMO

ATP-sensitive P2X(7) receptors are localized on cells of immunological origin including glial cells in the central nervous system. Activation of P2X(7) receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1beta (IL-1beta), and following prolonged agonist exposure, cytolytic plasma membrane pore formation. P2X(7) knockout mice show reduced inflammation as well as decreased nociceptive sensitivity following peripheral nerve injury. A-740003 (N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide) is a novel competitive antagonist of P2X(7) receptors (IC(50) values = 40 nM for human and 18 nM for rat) as measured by agonist-stimulated changes in intracellular calcium concentrations. A-740003 showed weak or no activity (IC(50) > 10 muM) at other P2 receptors and an array of other neurotransmitter and peptide receptors, ion channels, reuptake sites, and enzymes. A-740003 potently blocked agonist-evoked IL-1beta release (IC(50) = 156 nM) and pore formation (IC(50) = 92 nM) in differentiated human THP-1 cells. Systemic administration of A-740003 produced dose-dependent antinociception in a spinal nerve ligation model (ED(50) = 19 mg/kg i.p.) in the rat. A-740003 also attenuated tactile allodynia in two other models of neuropathic pain, chronic constriction injury of the sciatic nerve and vincristine-induced neuropathy. In addition, A-740003 effectively reduced thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED(50) = 38-54 mg/kg i.p.). A-740003 was ineffective in attenuating acute thermal nociception in normal rats and did not alter motor performance at analgesic doses. These data demonstrate that selective blockade of P2X(7) receptors in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.


Assuntos
Acetamidas/farmacologia , Analgésicos , Dor/tratamento farmacológico , Dor/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Antagonistas do Receptor Purinérgico P2 , Quinolinas/farmacologia , Animais , Antineoplásicos Fitogênicos/toxicidade , Cálcio/metabolismo , Linhagem Celular , Corantes , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Adjuvante de Freund/farmacologia , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X7 , Neuropatia Ciática/prevenção & controle , Nervos Espinhais/lesões , Vincristina/toxicidade
13.
J Pharmacol Exp Ther ; 314(1): 410-21, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15837818

RESUMO

The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 micromol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 micromol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 micromol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.


Assuntos
Analgésicos , Inflamação/complicações , Isoquinolinas/farmacologia , Dor/tratamento farmacológico , Receptores de Droga/antagonistas & inibidores , Ureia/análogos & derivados , Doença Aguda , Animais , Capsaicina , Carragenina , Doença Crônica , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/complicações , Formaldeído , Adjuvante de Freund , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Ligadura , Masculino , Atividade Motora/efeitos dos fármacos , Osteoartrite/complicações , Dor/etiologia , Medição da Dor/efeitos dos fármacos , Dor Pós-Operatória/tratamento farmacológico , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/patologia , Nervos Espinhais/patologia , Ureia/farmacologia
14.
Proc Natl Acad Sci U S A ; 99(26): 17179-84, 2002 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-12482951

RESUMO

P2X3 and P2X2/3 receptors are highly localized on peripheral and central processes of sensory afferent nerves, and activation of these channels contributes to the pronociceptive effects of ATP. A-317491 is a novel non-nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux (Ki = 22-92 nM) and was highly selective (IC50 >10 microM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dose-dependently (ED50 = 30 micromolkg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50 = 10-15 micromolkg s.c.) in attenuating both thermal hyperalgesia and mechanical allodynia after chronic nerve constriction injury. The R-enantiomer, A-317344, was inactive in these chronic pain models. Although active in chronic pain models, A-317491 was ineffective (ED50 >100 micromolkg s.c.) in reducing nociception in animal models of acute pain, postoperative pain, and visceral pain. The present data indicate that a potent and selective antagonist of P2X3 and P2X2/3 receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X3 and P2X2/3 receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain.


Assuntos
Analgésicos não Narcóticos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Fenóis/farmacologia , Compostos Policíclicos/farmacologia , Antagonistas do Receptor Purinérgico P2 , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Relação Dose-Resposta a Droga , Hemodinâmica/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X2 , Receptores Purinérgicos P2X3
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