RESUMO
N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5747) are novel δ-opioid agonists that show good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. Here, we used genetic approaches to investigate molecular mechanisms underlying their analgesic effects in the mouse. We tested analgesic effects of ADL5859 and ADL5747 in mice by using mechanical sensitivity measures in both complete Freund's adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in δ-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of δ-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical δ agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (SNC80) as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three δ-opioid agonists were abolished in constitutive δ-receptor KO mice and strongly diminished in δ-receptor cKO mice. We also measured two other well described effects of δ agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged δ receptors. In contrast to SNC80, ADL5859 and ADL5747 did not induce either hyperlocomotion or receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 showed efficient pain-reducing properties in the two models of chronic pain. Their effects were mediated by δ-opioid receptors, with a main contribution of receptors expressed on peripheral Nav1.8-positive neurons. The lack of in vivo receptor internalization and locomotor activation, typically induced by SNC80, suggests agonist-biased activity at the receptor for the two drugs.
Assuntos
Benzamidas/farmacologia , Benzopiranos/farmacologia , Locomoção/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Receptores Opioides delta/metabolismo , Compostos de Espiro/farmacologia , Analgesia/métodos , Analgésicos Opioides/agonistas , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Locomoção/genética , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Medição da Dor/métodos , Piperazinas/farmacologia , Receptores Opioides delta/genéticaAssuntos
Proteínas de Ligação ao GTP/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Animais , Células CHO , Linhagem Celular , Cricetinae , Proteínas de Ligação ao GTP/genética , Guanosina Difosfato/farmacologia , Cinética , Mamíferos , Ligação Proteica , Proteínas Recombinantes/metabolismo , Transdução de Sinais , SpodopteraRESUMO
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.