RESUMO
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Analgésicos/síntese química , Ansiolíticos/síntese química , Anticonvulsivantes/síntese química , Canais de Cálcio/metabolismo , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/síntese química , Aminas/antagonistas & inibidores , Aminas/metabolismo , Analgésicos/química , Analgésicos/farmacologia , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ácidos Cicloexanocarboxílicos/antagonistas & inibidores , Ácidos Cicloexanocarboxílicos/metabolismo , Gabapentina , Técnicas In Vitro , Leucina/antagonistas & inibidores , Leucina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pregabalina , Ligação Proteica , Subunidades Proteicas/metabolismo , Ratos , Relação Estrutura-Atividade , Suínos , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologiaRESUMO
Preparative chemical methods for the synthesis of eight oxidative transformation products of ethinyl estradiol (EE) and norethindrone acetate (NA) are described. The prepared materials are useful as reference materials and standards for pharmaceutical analysis of EE and NA as bulk chemical or in formulated product. All eight products result from oxidation of the A and/or B rings of the parent compounds. Oxidation of the heteroannular 3,5 dienyl acetate derivative of NA resulted in the 6 alpha-hydroxy, 6 beta-hydroxy and 6-keto NA. Oxidation of 6-keto NA led to the preparation of 6 alpha-hydroxy, 6 beta-hydroxy, 6-keto- and Delta(6) EE. Delta(11) EE was prepared from estrone.