RESUMO
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Dor/tratamento farmacológico , Sulfonas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Antagonistas de Receptor B2 da Bradicinina , Doença Crônica , Humanos , Coelhos , Ratos , Ratos Sprague-Dawley , Sulfonas/administração & dosagemRESUMO
The discovery of novel analgesic compounds that target some receptors can be challenging due to species differences in ligand pharmacology. If a putative analgesic compound has markedly lower affinity for rodent versus other mammalian orthologs of a receptor, the evaluation of antinociceptive efficacy in non-rodent species becomes necessary. Here, we describe a new, efficient method for measuring inflammation-associated nociception in conscious rabbits. An electronic von Frey device is used, consisting of a rigid plastic tip connected to a force transducer in a hand-held probe. The plastic tip is applied to the plantar surface of a hind paw with increasing force until a withdrawal response is observed. The maximum force (g) tolerated by the rabbit (i.e., withdrawal threshold) is recorded. In young, conscious rabbits (500-700 g), baseline hind paw withdrawal thresholds typically fell within the 60-80 g range. Three hours after injection of the inflammatory agent carrageenan (3%, 200 microL, intra-plantar), withdrawal thresholds dropped by approximately 30-40 g, indicating the presence of punctate mechanical hyperalgesia. The development of hyperalgesia was dose dependently prevented by the NSAID indomethacin (ED50=2.56 mg/kg, p.o.) or the bradykinin B2 receptor peptide antagonist HOE 140 (intra-paw administration). An established hyperalgesia was dose dependently reversed by morphine sulfate (ED50=0.096 mg/kg, s.c.) or the bradykinin B1 receptor peptide antagonist [des-Arg10, Leu9]-kallidin (ED50=0.45 mg/kg, s.c.). Rabbits treated with the novel B(1) receptor small molecule antagonist compound A also showed dose-dependent reversal of hyperalgesia (ED50=20.19 mg/kg, s.c.) and analysis of plasma samples taken from these rabbits showed that, unlike other rabbit pain models, the current method permits the evaluation of pharmacokinetic-pharmacodynamic (PK-PD) relationships (compound A plasma EC50=402.6 nM). We conclude that the Electrovonfrey method can be used in rabbits with inflammatory pain to generate reliable dose- and plasma concentration-effect curves for different classes of analgesics.
Assuntos
Hiperalgesia/etiologia , Hiperalgesia/patologia , Metacarpo/fisiopatologia , Medição da Dor/métodos , Dor/complicações , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Carragenina , Relação Dose-Resposta a Droga , Interações Medicamentosas , Éteres/sangue , Hidrocarbonetos Fluorados/sangue , Hiperalgesia/prevenção & controle , Indometacina/administração & dosagem , Inflamação/induzido quimicamente , Inflamação/complicações , Calidina/administração & dosagem , Calidina/análogos & derivados , Metacarpo/efeitos dos fármacos , Dor/etiologia , Medição da Dor/instrumentação , Limiar da Dor/efeitos dos fármacos , Coelhos , Tempo de Reação/efeitos dos fármacos , Análise Espectral , Fatores de TempoRESUMO
The bradykinin B1 receptor is an inducible G-protein-coupled receptor. It is induced or upregulated at the site of inflammation or injury. A large body of preclinical data supports the development of B1 antagonists as novel therapeutics for the treatment of pain and inflammation. The necessary in vitro and in vivo drug discovery tools are currently available to evaluate novel B1 antagonists. Two major classes of small-molecule B1 antagonists, arylsulfonamide-based and biphenyl-based B1 antagonists, have been disclosed in the last few years.