RESUMO
Nonselective glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) γ8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of γ8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant γ8-containing AMPA receptors was modulated by coexpression with other TARPs; γ2 subunits affected activity more than γ3 subunits. Consistent with these findings, LY3130481 had decreasing potency on receptors from rat hippocampal, cortical, spinal cord, and cerebellar neurons that was replicated in tissue from human brain. LY3130481 partially suppressed, whereas the nonselective AMPA antagonist GYKI53784 completely blocked, AMPA receptor-dependent excitatory postsynaptic potentials in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response to stimulation of peripheral afferents. LY3130481 also significantly reduced nocifensive behaviors after intraplantar formalin that was correlated with occupancy of CNS γ8-containing AMPA receptors. In addition, LY3130481 dose-dependently attenuated established gait impairment after joint damage and tactile allodynia after spinal nerve ligation, all in the absence of motor side effects. Collectively, these data demonstrate that LY3130481 can suppress excitatory synaptic transmission and plasticity in pain pathways containing γ8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective, and safer therapy for chronic pain conditions.
Assuntos
Canais de Cálcio/metabolismo , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Terapia de Alvo Molecular , Receptores de AMPA/metabolismo , Animais , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Dor Crônica/fisiopatologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Distribuição TecidualRESUMO
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.
Assuntos
Amidas/química , Amidas/farmacologia , Ciclopropanos/química , Ciclopropanos/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Amidas/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Ciclopropanos/farmacocinética , Ácido Glutâmico/química , Ácido Glutâmico/metabolismo , Indazóis/química , Indazóis/farmacocinética , Indazóis/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/química , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
Assuntos
Isoquinolinas/farmacologia , Dor/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores de Ácido Caínico/antagonistas & inibidores , Tetrazóis/farmacologia , Administração Oral , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Isoquinolinas/química , Masculino , Dados de Sequência Molecular , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Receptores de Ácido Caínico/química , Relação Estrutura-Atividade , Tetrazóis/químicaRESUMO
The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
Assuntos
Isoquinolinas/farmacologia , Dor/tratamento farmacológico , Pró-Fármacos/farmacologia , Receptores de Ácido Caínico/antagonistas & inibidores , Administração Oral , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Haplorrinos , Isoquinolinas/química , Dados de Sequência Molecular , Pró-Fármacos/química , Receptores de Ácido Caínico/química , Relação Estrutura-AtividadeRESUMO
The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.
Assuntos
Amidas/síntese química , Analgésicos/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Dor/tratamento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiazóis/síntese química , Administração Oral , Amidas/administração & dosagem , Amidas/farmacocinética , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Humanos , Dor/metabolismo , Medição da Dor , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/administração & dosagem , Tiazóis/farmacocinéticaRESUMO
Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.
Assuntos
Aminoácidos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Dor/tratamento farmacológico , Receptores de Ácido Caínico/antagonistas & inibidores , Analgésicos/farmacocinética , Animais , Disponibilidade Biológica , Linhagem Celular , Modelos Animais de Doenças , Humanos , Hiperalgesia/tratamento farmacológico , Ratos , Receptores de AMPA/metabolismo , Proteínas Recombinantes/metabolismo , Medula Espinal/fisiopatologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
The involvement of Group II metabotropic receptors in acute and persistent pain states was evaluated in several in vivo models of pain with selective and potent Group II metabotropic glutamate (mGlu) 2,3 agonists. LY354740, LY379268 and LY389795 attenuated late-phase paw-licking pain behavior in a dose-dependent manner in the formalin model of persistent pain. Effects occurred in the absence of overt neuromuscular deficits as measured by performance in the rotorod test for ataxia. The effects of LY354740 and LY379268 were also stereoselective. The order of potency of the agonists was LY389795>LY379268>LY354740. The attenuation of licking behavior by LY379268 (3 mg/kg) in the formalin model was reversed by a potent and selective mGlu2,3 receptor antagonist, LY341495 (1 mg/kg). In the L5/L6 spinal nerve ligation model of neuropathic pain in rats, LY379268 significantly reversed mechanical allodynia behavior in a dose-related manner. In contrast, LY379268 had no significant effects on the tail flick test or paw withdrawal test of acute thermal nociceptive function. These results support the involvement of Group II mGlu2,3 receptors in persistent pain mechanisms and suggest the potential utility of selective Group II mGlu agonists for the treatment of persistent pain.
Assuntos
Agonistas de Aminoácidos Excitatórios/uso terapêutico , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/complicações , Receptores de Glutamato Metabotrópico/agonistas , Animais , Ataxia/induzido quimicamente , Ataxia/psicologia , Doença Crônica , Formaldeído , Injeções Intraperitoneais , Ligadura , Masculino , Dor/etiologia , Medição da Dor/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Nervos Espinhais/fisiologiaRESUMO
BACKGROUND: The rat L5/L6 spinal nerve ligation model (SNL) has been widely used to investigate putative analgesics. Pursuit of novel therapies in preclinical settings requires models with consistent and reproducible phenotypes. NEW METHOD: We assessed the effects of repetitive stimulation of the hindpaws of SNL and Sham surgery rats during the 2 weeks immediately after surgery on the overall rate of achieving tactile hypersensitivity, as well as the magnitude of the hypersensitivity compared to unprimed rats. Beginning on day 2 post-surgery, and continuing on alternate days for a total of seven sessions, animals underwent light brushing/tapping (termed priming) of the hindpaws ipsilateral and contralateral to surgery. RESULTS: Priming the ipsilateral hindpaw enhanced the magnitude of tactile hypersensitivity such that the baseline withdrawal threshold (BWT) for primed SNL animals was significantly lower than unprimed SNL animals over post-surgical days 15-29. BWT was not different between primed and unprimed Sham rats. The percentage of SNL primed animals meeting the a priori criterion for tactile hypersensitivity of paw withdrawal threshold less than 2.0 grams was 98.9%±1.1%. COMPARISON WITH EXISTING METHOD: SNL rats that did not receive stimulation (unprimed) showed significantly higher baseline hypersensitivity when evaluated on days 15-29, exemplified by only 34.5%±7.2% meeting the established <2.0g criterion. CONCLUSION: Our data indicate that tactile priming during the 2 weeks immediately after SNL surgery enhances the magnitude of tactile hypersensitivity in the SNL model, and provide an optimized assay for evaluating putative analgesics.
Assuntos
Modelos Animais de Doenças , Hiperalgesia/fisiopatologia , Estimulação Física/métodos , Nervos Espinhais/lesões , Nervos Espinhais/fisiopatologia , Aminas/farmacologia , Analgésicos/farmacologia , Animais , Ácidos Cicloexanocarboxílicos/farmacologia , Gabapentina , Membro Posterior/fisiopatologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Ligadura , Vértebras Lombares , Masculino , Medição da Dor , Limiar da Dor/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Sensibilidade e Especificidade , Nervos Espinhais/efeitos dos fármacos , Tato , Ácido gama-Aminobutírico/farmacologiaRESUMO
The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
RESUMO
5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in alpha-methyl-m-tyrosine-treated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.