RESUMO
G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation.
Assuntos
Cognição , Receptor A1 de Adenosina , Humanos , Adenosina , Sítios de Ligação , Coração , LigantesRESUMO
From an EtOAc-soluble fraction of the leaves of Azadirachta indica, one new lactam 28-norlimonoid named nimbandiolactam-21 (1), together with 2 known limonoids (2 and 3) were isolated. Their relative structures were elucidated based on NMR spectroscopic analysis. Nimbandiolactone-23 (2) showed the most potent α-glucosidase inhibitory activity, with an IC50 value of 38.7 µM. Compound 1 represents the first naturally occurring example of a 28-norlimonoid having the lactam moiety. The plausible biosynthetic pathway for the formation of lactam moiety in 1 was proposed.
Assuntos
Azadirachta/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Lactamas/farmacologia , Limoninas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Concentração Inibidora 50 , Lactamas/química , Lactamas/isolamento & purificação , Limoninas/química , Limoninas/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Folhas de Planta/química , Plantas Medicinais/químicaRESUMO
Agarwood, one of the valuable non-timber products in tropical forest, is a fragrant wood, whose ethereal fragrance has been prized in Asia for incense in ceremony, as well as sedatives in traditional medicine. We separated the 70% EtOH extract of Vietnamese agarwood, which showed significant induction effect on brain-derived neurotrophic factor (BDNF) mRNA expression in rat cultured neuronal cells, to isolate a new compound and a 2-(2-phenylethyl)chromone derivative. The new compound was determined to be a spirovetivane-type sesquiterpene, (4R,5R,7R)-1(10)-spirovetiven-11-ol-2-one, by spectroscopic data and showed induction effect of BDNF mRNA.