RESUMO
The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [(35)S]GTPγS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective κ opioid receptor antagonists.
Assuntos
Desenho de Fármacos , Antagonistas de Entorpecentes/síntese química , Piperidinas/química , Receptores Opioides kappa/antagonistas & inibidores , Tetra-Hidroisoquinolinas/química , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Células Madin Darby de Rim Canino , Antagonistas de Entorpecentes/metabolismo , Antagonistas de Entorpecentes/farmacocinética , Piperidinas/metabolismo , Piperidinas/farmacocinética , Ligação Proteica , Receptores Opioides kappa/metabolismo , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacocinéticaRESUMO
Procedures were developed for the synthesis of 3-methyl-5-phenylethynyl[1,2,4]triazine (4), 6-methyl-3-phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-phenylethynyl[1,2,4]triazine (6a) as analogues of 2-methyl-6-(phenylethynyl)pyridine (2). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The most potent of the three analogues was 6a. Twenty additional analogues of 6a were synthesized and evaluated for mGluR5 antagonist efficacy. The most potent compounds were 3-(3-methylphenylethynyl)-5-methyl[1,2,4]triazine (6b), 5-(3-chlorophenylethynyl)-5-methyl[1,2,4]triazine (6c), and 3-(3-bromophenylethynyl)-5-methyl[1,2,4]triazine (6d).