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1.
J Nat Prod ; 82(8): 2332-2336, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31385511

RESUMO

(11S)-11-Aminostrychnine (1) and N-[(11S)-strychnine-11-yl]propionamide (2) were synthesized and characterized as antagonists of homomeric α1 and heteromeric α1ß glycine receptors in a functional fluorescence-based assay and a patch-clamp assay and in radioligand binding studies. The absolute configuration at C-11 of 1 was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptor showed a binding mode of compound 2 analogous to that of strychnine, explaining its high antagonistic potency. The findings identify the C-11 amide function of strychnine as a suitable linker group for the future development of dimeric strychnine analogues targeting glycine receptors. The findings extend the SAR of strychnine at glycine receptors.


Assuntos
Amidas/química , Receptores de Glicina/antagonistas & inibidores , Estricnina/análogos & derivados , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Estricnina/farmacologia
2.
J Nat Prod ; 79(12): 2997-3005, 2016 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-27966945

RESUMO

A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1ß glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [3H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1ß antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.


Assuntos
Éteres/síntese química , Oximas/farmacologia , Receptores de Glicina/antagonistas & inibidores , Estricnina , Animais , Sítios de Ligação , Ligação Competitiva , Cristalografia por Raios X , Éteres/química , Éteres/farmacologia , Glicina/análise , Glicina/metabolismo , Humanos , Concentração Inibidora 50 , Ligantes , Conformação Molecular , Estrutura Molecular , Oximas/química , Relação Estrutura-Atividade , Estricnina/análogos & derivados , Estricnina/síntese química , Estricnina/química , Estricnina/farmacologia
3.
Chem Biodivers ; 11(8): 1256-62, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25146769

RESUMO

Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1ß glycine receptors were evaluated. Isostrychnine has shown the best pharmacological profile exhibiting an IC50 value of 1.6 µM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21) = C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine receptors.


Assuntos
Receptores de Glicina/antagonistas & inibidores , Relação Estrutura-Atividade , Estricnina/análogos & derivados , Técnicas de Química Sintética , Humanos , Concentração Inibidora 50 , Lactamas/química
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