RESUMO
A considerable number of research papers describing the synthesis and testing of the delta opioid receptor (DOR) ligands, SNC-80 and TAN-67, and analogues of these two compounds, have been published in recent years. However, there have been few reports of the discovery of completely new structural classes of selective DOR ligand. By optimising a hit compound identified by high throughput screening, a new series of tetrahydroisoquinoline sulphonamide-based delta opioid ligands was discovered. The main challenge in this series was to simultaneously improve both affinity and physicochemical properties, notably aqueous solubility. The most active ligand had an affinity (IC(50)) of 6 nM for the cloned human DOR, representing a 15-fold improvement relative to the original hit 1 (IC(50) 98 nM). Compounds from this new series show good selectivity for the DOR over mu and kappa opioid receptors. However the most active and selective compounds had poor aqueous solubility. Improved aqueous solubility was obtained by replacing the phthalimide group in 1 by basic groups, allowing the synthesis of salt forms. A series of compounds with improved affinity and solubility relative to 1 was identified and these compounds showed activity in an in vivo model of antinociception, the formalin paw test. In the case of compound 19, this analgesic activity was shown to be mediated primarily via a DOR mechanism. The most active compound in vivo, 46, showed superior potency in this test compared to the reference DOR ligand, TAN-67 and similar potency to morphine (68% and 58% inhibition in Phases 1 and 2, respectively, at a dose of 10 mmol/kg i.v.).
Assuntos
Benzamidas/farmacologia , Naltrexona/análogos & derivados , Piperazinas/farmacologia , Quinolinas/farmacologia , Receptores Opioides delta , Amidas/síntese química , Amidas/química , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Animais , Benzamidas/química , Encéfalo/metabolismo , Catálise , Técnicas de Química Combinatória , Cobaias , Humanos , Concentração Inibidora 50 , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacologia , Ligantes , Masculino , Maleimidas/química , Maleimidas/farmacologia , Proteínas de Membrana/análise , Proteínas de Membrana/química , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Morfina/farmacologia , Naltrexona/química , Naltrexona/farmacologia , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/química , Medição da Dor , Ftalimidas/química , Ftalimidas/farmacologia , Piperazinas/química , Quinolinas/química , Ratos , Ratos Wistar , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides delta/genética , Receptores Opioides delta/metabolismo , Relação Estrutura-Atividade , Succinimidas/química , Succinimidas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologiaAssuntos
Sistemas de Transporte de Aminoácidos Neutros , Benzamidas/síntese química , Proteínas de Transporte/antagonistas & inibidores , Glicina/metabolismo , Animais , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Técnicas de Química Combinatória , Proteínas da Membrana Plasmática de Transporte de Glicina , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Relação Estrutura-AtividadeRESUMO
Two focused libraries of delta opioid ligands were synthesised using AlCl3 facilitated aminolysis. Several compounds were identified with DOR binding affinities higher or similar to SNC-80. A novel acyclic derivative of SNC-80 produced antinociception in the acetic acid abdominal constriction test, which is at least partially mediated via the delta-opioid receptor.
