RESUMO
A series of 3'-(substituted phenyl)deschloroepibatidine analogs (5a-j) were synthesized. The alpha4beta2( *) and alpha7 nicotinic acetylcholine receptor (nAChR) binding properties and functional activity in the tail-flick, hot-plate, locomotor, and body temperature tests in mice of 5a-j were compared to those of the nAChR agonist, nicotine (1), epibatidine (4), and deschloroepibatidine (13), the partial agonist, varenicline (3), and the antagonist 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogs (7a-j). Unlike epibatidine and deschloroepibatidine, which are potent agonists in the tail-flick test, 5a-k show no or very low antinociceptive activity in the tail-flick or hot-plate test. However, they are potent antagonists in nicotine-induced antinociception in the tail-flick test, but weaker than the corresponding 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines.
Assuntos
Analgésicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Antagonistas Nicotínicos/síntese química , Piridinas/síntese química , Receptores Nicotínicos/metabolismo , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Temperatura Corporal , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacologia , Dor/prevenção & controle , Ligação Proteica , Piridinas/metabolismo , Piridinas/farmacologia , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
A series of 3'-substituted deschloroepibatidine analogues (3a-g and 4) showed high affinity for alpha4beta2 binding and relatively weak affinity for alpha7 nAChRs. The 3'-ethynyl (3g) and 3'-fluoro (3a) analogues with K(i) values of 0.02 and 0.037 nM, respectively, were the most potent. Even though the alpha4beta2 binding affinity of several of the analogues were equal to that of epibatidine, all of the compounds were weak agonists in the antinociceptive, hypothermia, and spontaneous activity test in mice. In contrast, all of the compounds were functional antagonists of nicotine-induced antinociception. In general, compounds 3a-g and 4 were more potent in the tail-flick assay than the hot-plate test. For example, the 3'-fluoro analogue 3a and the N-methyl-3'-iodo analogue 4 showed AD(50) values of 0.07 and 0.04 microg/kg, respectively, in the tail flick test and only 35 and 0% inhibition at 20 and 10 microg/kg in the hot-plate assay, respectively. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. The high affinity of the N-methyl-3'-iodo analogue 4 combined with its weak agonist and potent antagonist activity suggests that carbon-11 and iodine-123 analogues may be useful as PET and SPECT ligands, respectively, for studying nAChRs in vivo.
Assuntos
Analgésicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Antagonistas Nicotínicos/síntese química , Piridinas/síntese química , Receptores Nicotínicos/metabolismo , Analgésicos/química , Analgésicos/farmacologia , Animais , Ligação Competitiva , Temperatura Corporal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacologia , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Receptores Nicotínicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Using positron emission tomography (PET) with a specific and selective radioligand targeting nicotinic acetylcholine receptor (nAChR) would allow us to better understand various nAChR related CNS disorders. The use of radiolabeled nAChR antagonists would provide a much safer pharmacological profile, avoiding most peripheral side effects that might be generated from radiolabeled nAChR agonists even at the tracer level; thus, PET imaging with nAChR antagonists would facilitate clinical application. A potent and selective nAChR antagonist was labeled and characterized with PET in non-human primates. Its high brain uptake, high signal-to-noise ratio, and high specific binding strongly suggest a great potential to carry out imaging studies in humans. In addition, the use of a C-11 radiotracer would allow us to perform multiple PET studies in the same individual within a short time frame. The presence of an iodine atom in the molecule also allows the possibility to label with radioiodine for SPECT studies.
Assuntos
Encéfalo/diagnóstico por imagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Antagonistas Nicotínicos/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Receptores Nicotínicos/efeitos dos fármacos , Animais , Ligação Competitiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Radioisótopos de Carbono , Avaliação Pré-Clínica de Medicamentos , Ligantes , Estrutura Molecular , Nicotina/farmacocinética , Antagonistas Nicotínicos/síntese química , Antagonistas Nicotínicos/química , Papio , Relação Estrutura-Atividade , Fatores de TempoRESUMO
The natural product withaferin A (WFA) is a potent angiogenesis inhibitor and it targets the ubiquitin-proteasome pathway in vascular endothelial cells. We generated a biotinylated affinity analog WFA-LC(2)B for use as a probe to study angiogenesis. WFA-LC(2)B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-alpha-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC(2)B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC(2)B analog will be useful to isolate the biological target of WFA.