RESUMO
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Assuntos
Naftiridinas/síntese química , Naftiridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/fisiologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Indicadores e Reagentes , Articulações/patologia , Lactonas/uso terapêutico , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-Atividade , Sulfonas/uso terapêuticoRESUMO
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Assuntos
Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
Previously, we reported on PD 102807 (41) as being the most selective synthetic M(4) muscarinic antagonist identified to date. Synthesized analogues of 41 showed no improvement in affinity and selectivity at that time. However, several newly synthesized compounds exhibit a 7-fold higher affinity at M(4) receptors and demonstrate a selectivity of at least 100-fold over all other muscarinic receptor subtypes. For example, compound 28 showed an affinity of pK(i) = 9.00 at M(4) receptors and a selectivity of M(1)/M(4) = 13 183-fold, M(2)/M(4) = 339-fold, M(3)/M(4) = 151-fold, and M(5)/M(4) = 11 220-fold. This high selectivity along with high affinity has not been reported for any synthetic muscarinic antagonist, nor for natural occurring M(4) antagonists such as the M(4) selective Eastern Green Mamba venom MT3 (M(4) pK(b) = 8.7, M(1)/M(4) = 40-fold, M(2)/M(4) > or = 500-fold, M(3)/M(4) > or = 500-fold, and M(5)/M(4) > or = 500-fold). Derivative 24, a compound with a high selectivity pattern as well, has been tested for in vivo efficacy. It was able to block the L-3,4-dihydroxyphenylalanine accumulation produced by CI-1017, an M(1)/M(4) selective muscarinic agonist, in the mesolimbic region and striatum, which suggests that 24 is capable of crossing the blood-brain barrier and confirms the pharmacokinetic data obtained on this compound. This is evidence that suggests that agonist-induced increase in catecholamine synthesis observed in these regions is mediated by M(4) receptors.