RESUMO
Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage. The development of OIH and tolerance tend to occur simultaneously and, thus, present a challenge when studying the molecular mechanisms driving each phenomenon. We tested the hypothesis that a G protein-biased µ-opioid peptide receptor (MOPR) agonist would not induce symptoms of OIH, such as mechanical allodynia, following chronic administration. We observed that the development of opioid-induced mechanical allodynia (OIMA), a model of OIH, was absent in ß-arrestin1-/- and ß-arrestin2-/- mice in response to chronic administration of conventional opioids such as morphine, oxycodone and fentanyl, whereas tolerance developed independent of OIMA. In agreement with the ß-arrestin knockout mouse studies, chronic administration of TRV0109101, a G protein-biased MOPR ligand and structural analog of oliceridine, did not promote the development of OIMA but did result in drug tolerance. Interestingly, following induction of OIMA by morphine or fentanyl, TRV0109101 was able to rapidly reverse allodynia. These observations establish a role for ß-arrestins in the development of OIH, independent of tolerance, and suggest that the use of G protein-biased MOPR ligands, such as oliceridine and TRV0109101, may be an effective therapeutic avenue for managing chronic pain with reduced propensity for opioid-induced hyperalgesia.
Assuntos
Analgésicos Opioides/administração & dosagem , Proteínas de Ligação ao GTP/agonistas , Hiperalgesia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Receptores Opioides mu/agonistas , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Proteínas de Ligação ao GTP/fisiologia , Células HEK293 , Humanos , Hiperalgesia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/métodos , Receptores Opioides mu/fisiologiaRESUMO
The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in ß-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the µ-opioid receptor (MOR) to G proteins, but not ß-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less ß-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain.
Assuntos
Analgésicos/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Morfina/farmacologia , Receptores Opioides mu/metabolismo , Sistema Respiratório/efeitos dos fármacos , Animais , Arrestinas/metabolismo , Linhagem Celular , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/metabolismo , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/metabolismo , Transdução de Sinais/efeitos dos fármacos , beta-Arrestina 2 , beta-ArrestinasRESUMO
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Assuntos
Compostos de Anilina/química , Benzamidas/química , Receptor CB2 de Canabinoide/agonistas , Sulfonamidas/química , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain.
Assuntos
Anti-Inflamatórios/química , Benzamidas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Descoberta de Drogas , Humanos , Dor Pós-Operatória/tratamento farmacológico , Ratos , Receptor CB2 de Canabinoide/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.
Assuntos
Aminopiridinas/química , Morfolinas/química , Piridinas/química , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Animais , Cães , Humanos , Masculino , Microssomos Hepáticos , Morfolinas/síntese química , Morfolinas/farmacologia , Dor/tratamento farmacológico , Ligação Proteica , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Assuntos
Benzamidas/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Benzamidas/uso terapêutico , Dor/tratamento farmacológico , RoedoresRESUMO
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.
Assuntos
Benzamidas/uso terapêutico , Neuralgia/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , Sulfonamidas/uso terapêutico , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Relação Dose-Resposta a Droga , Ligantes , Camundongos , Modelos Animais , Modelos Químicos , Medição da Dor/efeitos dos fármacos , Ratos , Receptor CB2 de Canabinoide/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform-selective inhibitors of NOS have been developed. The present experiments examined the anti-inflammatory and antinociceptive activity of a selective inducible nitric oxide (iNOS) inhibitor, AR-C102222, on arachidonic acid-induced ear inflammation, Freund's complete adjuvant (FCA)-induced hyperalgesia, acetic acid-induced writhing, and tactile allodynia produced by L5 spinal nerve ligation (L5 SNL) or hindpaw incision (INC). AR-C102222 at a dose of 100mg/kg p.o., significantly reduced inflammation produced by the application of arachidonic acid to the ear, attenuated FCA-induced mechanical hyperalgesia, and attenuated acetic acid-induced writhing. In the L5 SNL and INC surgical procedures, tactile allodynia produced by both procedures was significantly reduced by 30mg/kg i.p. of AR-C102222. These data demonstrate that the selective inhibition of iNOS produces antinociception in different models of pain and suggest that the iNOS-NO system plays a role in pain processing.
Assuntos
Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Mononeuropatias/tratamento farmacológico , Óxido Nítrico Sintase/antagonistas & inibidores , Dor/tratamento farmacológico , Quinazolinas/uso terapêutico , Animais , Modelos Animais de Doenças , Inflamação/complicações , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Mononeuropatias/complicações , Dor/etiologia , Ratos , Ratos Sprague-DawleyRESUMO
The identification of peripherally expressed CB2 receptors and reports that the selective activation of cannabinoid CB2 receptors produces antinociception without traditional cannabinergic side effects suggests that selective cannabinoid CB2 receptor agonists might be useful in the management of pain. In a rat hindpaw incision model, we examined the antiallodynic activity of the selective cannabinoid CB2 receptor agonists AM1241 (3-30 mg/kg i.p.), GW405833 (3-30 mg/kg i.p.), and HU-308 (0.3-30 mg/kg i.p.). The rank order for efficacy in the hindpaw incision model following a dose of 10 mg/kg, i.p. was AM1241 > GW405833 = HU-308, and the selective cannabinoid CB2 receptor antagonist, SR144528, reversed the antiallodynic effect of HU-308. Together, these data suggest that selective cannabinoid CB2 receptor agonists might represent a new class of postoperative analgesics.
Assuntos
Membro Posterior/cirurgia , Dor Pós-Operatória/prevenção & controle , Receptor CB2 de Canabinoide/agonistas , Animais , Canfanos/administração & dosagem , Canfanos/uso terapêutico , Canabinoides/administração & dosagem , Canabinoides/uso terapêutico , Esquema de Medicação , Traumatismos do Pé/cirurgia , Indóis/administração & dosagem , Indóis/uso terapêutico , Masculino , Modelos Animais , Morfolinas/administração & dosagem , Morfolinas/uso terapêutico , Dor/prevenção & controle , Medição da Dor/métodos , Dor Pós-Operatória/fisiopatologia , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/antagonistas & inibidores , Fatores de TempoRESUMO
The concept of "ligand bias" at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical µ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in ß-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased µ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased µ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.
Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/farmacologia , Descoberta de Drogas/métodos , Receptores Opioides mu/agonistas , Compostos de Espiro/farmacologia , Tiofenos/farmacologia , Dor Aguda/patologia , Analgésicos/síntese química , Analgésicos/química , Animais , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Camundongos , Modelos Químicos , Estrutura Molecular , Ratos , Receptores Opioides mu/metabolismo , Índice de Gravidade de Doença , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Assuntos
Analgésicos/farmacologia , Analgésicos/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzopiranos/farmacologia , Benzopiranos/uso terapêutico , Dor/tratamento farmacológico , Receptores Opioides delta/agonistas , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Benzopiranos/administração & dosagem , Benzopiranos/química , Células CHO , Ensaios Clínicos como Assunto , Cricetinae , Cricetulus , Cristalografia por Raios X , Inibidores do Citocromo P-450 CYP2D6 , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/administração & dosagem , Compostos de Espiro/químicaRESUMO
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Assuntos
Analgésicos/administração & dosagem , Benzamidas/administração & dosagem , Benzopiranos/administração & dosagem , Dor/tratamento farmacológico , Receptores Opioides delta/agonistas , Administração Oral , Analgésicos/síntese química , Analgésicos/química , Animais , Benzamidas/síntese química , Benzamidas/química , Benzopiranos/síntese química , Benzopiranos/química , Disponibilidade Biológica , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Dose Máxima Tolerável , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Ratos , Testes de ToxicidadeRESUMO
A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.
Assuntos
Química Farmacêutica/métodos , Malonatos/síntese química , Malonatos/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Citocromo P-450 CYP2D6/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Cinética , Malonatos/química , Modelos Químicos , Conformação MolecularRESUMO
A series of 3-substituted analogs (3) of the parent kappa agonist, 1, were prepared to limit access to the central nervous system. With the exception of compound 3j, all other compounds bound to the human kappa opioid receptor with high affinity (K(i)=0.31-9.5 nM) and were selective for kappa over mu and delta opioid receptors. Compounds 3c, d, and 3g-i produced potent antinociceptive activity in the rat formalin assay (i.paw) and the mouse acetic acid-induced writhing assay (s.c.), with weak activity in the mouse platform sedation test. The peripheral restriction indices of 3c, d, 3g, and 3i were improved 2- to 7-fold compared to the parent compound 1, and these compounds were approximately 2- to 5-fold more potent than the peripheral kappa agonist ICI 204448.
Assuntos
Analgésicos/síntese química , Pirrolidinas/síntese química , Receptores Opioides kappa/agonistas , Amidas/síntese química , Amidas/farmacologia , Analgésicos/farmacologia , Animais , Sistema Nervoso Central/metabolismo , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Dor/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Pirrolidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A new class of kappa-opioid receptor agonists is described. The design of these agents was based upon energy minimization and structural overlay studies of the generic azepin-2-one structure 3 with the crystal structure of arylacetamide kappa agonist 1, ICI 199441. The most active compound identified was ligand 4a (K(i)=0.34 nM), which demonstrated potent antinociceptive activity after oral administration in rodents.