RESUMO
Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14- O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent µ/δ opioid receptor (MOR/DOR) agonists with peripheral antinociceptive efficacy is reported. The current study adds significant value to our initial structure-activity relationships on a series of zwitterionic analogues of 1 (14- O-methyloxymorphone) by targeting additional amino acid residues. The new derivatives showed high binding and potent agonism at MOR and DOR in vitro. In vivo, the new 6-amino acid- and 6-dipeptide-substituted derivatives of 1 were highly effective in inducing antinociception in the writhing test in mice after subcutaneous administration, which was antagonized by naloxone methiodide demonstrating activation of peripheral opioid receptors. Such peripheral opioid analgesics may represent alternatives to presently available drugs for a safer pain therapy.
Assuntos
Analgésicos Opioides/síntese química , Oximorfona/análogos & derivados , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Membrana Celular/metabolismo , Dipeptídeos/química , Humanos , Masculino , Camundongos , Morfina/uso terapêutico , Oximorfona/química , Oximorfona/metabolismo , Oximorfona/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/patologia , Ligação Proteica , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) alpha,gamma-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Replicação Viral/efeitos dos fármacos , Linhagem Celular Tumoral , DNA Helicases/antagonistas & inibidores , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Testes de Sensibilidade Microbiana/métodos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Replicon/efeitos dos fármacos , Replicon/genéticaRESUMO
Ethyl 2-methylimidazo[1,2-a]pyrrolo[2,3-c]pyridin-8-carboxylate (AG110) was identified as a potent inhibitor of pestivirus replication. The 50% effective concentration values for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect, viral RNA synthesis, and production of infectious virus were 1.2 +/- 0.5 microM, 5 +/- 1 microM, and 2.3 +/- 0.3 microM, respectively. AG110 proved inactive against the hepatitis C virus and a flavivirus. AG110 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carry the E291G mutation in the viral RNA-dependent RNA polymerase (RdRp). AG110-resistant virus is cross-resistant to the cyclic urea compound 1453 which also selects for the E291G drug resistance mutation. Moreover, BVDV that carries the F224S mutation (because of resistance to the imidazopyridine 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine [BPIP]and VP32947) is also resistant to AG110. AG110 did not inhibit the in vitro activity of recombinant BVDV RdRp but inhibited the activity of BVDV replication complexes (RCs). Molecular modeling revealed that E291 is located in a small cavity near the tip of the finger domain of the RdRp about 7 A away from F224. Docking of AG110 in the crystal structure of the BVDV RdRp revealed several potential contacts including with Y257. The E291G mutation might enable the free rotation of Y257, which might in turn destabilize the backbone of the loop formed by residues 223 to 226, rendering more mobility to F224 and, hence, reducing the affinity for BPIP and VP32947. It is concluded that a single drug-binding pocket exists within the finger domain region of the BVDV RdRp that consists of two separate but potentially overlapping binding sites rather than two distinct drug-binding pockets.