RESUMO
The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Agonistas Muscarínicos/síntese química , Agonistas Muscarínicos/farmacologia , Oximas/síntese química , Oximas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Animais , Clonagem Molecular , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Receptor Muscarínico M1 , Receptores Muscarínicos/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacosRESUMO
The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Desenho de Fármacos , Agonistas Muscarínicos/síntese química , Oximas/síntese química , Receptores Muscarínicos/efeitos dos fármacos , Células 3T3 , Inibidores de Adenilil Ciclases , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/toxicidade , Células CHO , Cricetinae , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Humanos , Fosfatos de Inositol/biossíntese , Masculino , Memória/efeitos dos fármacos , Camundongos , Agonistas Muscarínicos/metabolismo , Agonistas Muscarínicos/farmacologia , Agonistas Muscarínicos/toxicidade , Oximas/metabolismo , Oximas/farmacologia , Oximas/toxicidade , Ratos , Receptor Muscarínico M1 , Receptores Muscarínicos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
The synthesis of a series of potent and efficacious 1-azabicyclo[2.2.1]heptan-3-one oxime muscarinic agonists is described. The oximes have extended appendages designed to span the cavity defined by the seven transmembrane helices of the muscarinic receptor. Some members of the series are selective for receptors of the m1 subtype. One such oxime, 31, shows affinity and functional selectivity for m1 over m2, m3, and m4 muscarinic receptor types.
