In Vitro and In Vivo Metabolism and Inhibitory Activities of Vasicine, a Potent Acetylcholinesterase and Butyrylcholinesterase Inhibitor

Abstract

Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer’s disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity.

Anti-amnesic effect of extract and alkaloid fraction from aerial parts of Peganum harmala on scopolamine-induced memory deficits in mice

“…And the drug-contain plasma samples could produce significantly cholinesterase inhibition activity and maintain for 2 h at least, after the once intravenously administration 2 mg/kg vasicine (Liu et al, , 2015c. These results suggested that vasicine and other analogs alkaloids were the main potential active ingredients in ALK and EXT from APP for treatment forgetfulness by inhibiting the activity of AChE and increasing the content of neurotransmitter ACh in cortex and hippocampus.…”

Biologically active quinoline and quinazoline alkaloids part II

“…harmala showed potent AChE (IC 50 = 2.37 and 0.04 μM, respectively) and BChE (IC 50 = 3.38 and 0.1 μM, respectively) inhibitory activity, but deoxyvasicinone, vasicinone, and 2‐carboxyl‐3,4‐dihydroquinazoline were inactive . Vasicine undergoes metabolic inactivation in vivo in respect to cholinesterase inhibitory activity, as most of its main metabolites were weaker inhibitors of AChE and BChE . In studies on the seeds of P. nigellastrum , two new alkaloids nigellastrine I ( 218 ) and nigellastrine II ( 219 ) (Figure ), along with, vasicinone, vasicine, deoxyvasicinone, deoxyvasicine, showed good inhibitory effects against AChE .…”

Antitussive, expectorant, and bronchodilating effects of quinazoline alkaloids (±)-vasicine, deoxyvasicine, and (±)-vasicinone from aerial parts of Peganum harmala L

“…VAS and DVAS respectively provided a single spot on TLC over silica gel at Rf = 0.52 and Rf = 0.41, respectively, with methanol-dichloromethane-ammonia mixtures (3:2:0.1) as the developing system, and the spots turned orange red upon spraying with Dragendorff's reagent. The actual structures of VAS and DVAS were characterized by NMR data, mass spectral data, and by comparing with standard compounds (Plugar et al, 1983;Liu et al, 2015b).…”

“…The detection wavelength was set at 280 nm. VAO (522 mg) was characterized by NMR data, mass spectral data, and by comparison with standard compounds (Liu et al, 2015b). The structures of VAS, DVAS and VAO are showed in Fig.…”

“…Previous phytochemical studies showed that quinazoline alkaloids and flavonoids are the major constituents of APP, and among alkaloids, vasicine (VAS) and deoxyvasicine (DVAS) are the main ones. Of them, VAS can be spontaneously oxidized to vasicinone (VAO) (Duan et al, 1998;Liu et al, 2015b;Rachana et al, 2011;Sharma et al, 1983). Previous in vitro studies showed that the crude extracts of APP, containing VAS, DVAS, harmine and harmaline, may have effective anti-asthmatic activities (Amin and Mehta, 1959;Hider et al, 1981;Nie et al, 2004).…”