RESUMO
With an aim to disclose the convergency and flexibility of our previously explored synthetic route to natural himbacine 1, and moreover, to clarify some novel aspects of the structure-activity relationships of 1, we prepared various structural types of novel himbacine congeners, 3-demethylhimbacine (3-norhimbacine) 2 and 4-epi-3-demethylhimbacine (4-epi-3-norhimbacine) 4-epi-2 and their enantiomers (ent-2 and ent-4-epi-2), 11-methylhimbacine 3, and 3-epihimbacine 4 in optically pure forms by employing our methodology. All of the synthesized congeners correspond to the compounds modified at the C-3 position of gamma-lactone moiety involved in 1. Among these congeners, 3-demethylhimbacine (3-norhimbacine) 2 was found to exhibit more potent muscarinic M(2) receptor binding affinity than natural 1.
Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Animais , Ligação Competitiva/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Furanos , Técnicas In Vitro , Indicadores e Reagentes , Cinética , Lactonas/síntese química , Lactonas/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Naftalenos , Piperidinas , Quinuclidinil Benzilato , Ratos , Receptor Muscarínico M2 , EstereoisomerismoRESUMO
In the course of our studies of the structure-activity relationships of himbacine 1, a potent antagonist of the M(2) subtype of muscarinic receptor, the four title compounds, 2, ent-2, 3, and ent-3, were synthesized with a highly stereoselective intermolecular Diels-Alder reaction of tetrahydroisobenzofuran 4 with achiral furan-2(5H)-one 5 as a key step, followed by simultaneous optical resolution and epimer separation of the racemic intermediates. Among these compounds, 3-demethylhimbacine (3-norhimbacine) 2, bearing an absolute configuration corresponding to that of 1, was found to show more potent muscarinic M(2) subtype receptor binding activity than natural 1.
Assuntos
Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/química , Alcaloides/síntese química , Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Tronco Encefálico/química , Córtex Cerebral/química , Furanos/farmacologia , Naftalenos , Parassimpatolíticos/síntese química , Parassimpatolíticos/farmacologia , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Receptor Muscarínico M2 , Receptores Muscarínicos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The title three compounds ent-1, 6, and ent-6 were synthesized by coupling the chiral sulfone 4 or ent-4 with the chiral piperidinaldehyde 5 or ent-5, which were readily prepared following the synthetic routes previously established by the novel total synthesis of natural himbacine 1. Their muscarinic M2 subtype binding affinity was evaluated in comparison to that of 1, disclosing that the stereochemistry of both the tricyclic moiety and the piperidine part of 1 plays crucial roles in its potent activity.