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ACS Chem Neurosci ; 10(3): 1380-1389, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30375852

RESUMO

Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT3 receptors (e.g., partial agonist, agonist, superagonist). Here, we demonstrate that conformational constraint of these agents as dihydroquinazolines (such as A6CDQ; 1) results in their conversion to 5-HT3 receptor antagonists. We examined the structure-activity relationships of 1. Replacement/removal of any of the guanidinium nitrogen atoms of 1 resulted in decreased affinity. All three nitrogen atoms of 1 are necessary for optimal binding affinity at 5-HT3 receptors. Introduction of substituents as small as an N2-methyl group abolishes affinity. The results are consistent with homology modeling/docking studies and binding data from site-directed mutagenesis studies. Introducing a "methylene bridge" to the arylguanidine structure, regardless of its functional activity, results in a 5-HT3 receptor antagonist.


Assuntos
Guanidinas/metabolismo , Metano/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Guanidinas/química , Células HEK293 , Humanos , Metano/química , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores 5-HT3 de Serotonina/química , Antagonistas do Receptor 5-HT3 de Serotonina/química , Xenopus
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