Papaveroline

Papaveroline is a Fyn tyrosine kinase inhibitor, Na +,K + -ATPase inhibitor with an IC₅₀ of 0.20 mM, Mg 2+ -ATPase inhibitor, K + -activated pNPPase inhibitor with an IC₅₀ of 1.51 mM, and apoptosis inducer ^{[1] [2] [3]}. Papaveroline binds to the active site of Fyn tyrosine kinase and forms stable interactions with pocket amino acid residues ^[1]. Papaveroline induces cell apoptosis, produces pycnotic and fragmented cell nuclei, and does not reduce intracellular ATP levels ^[3]. Papaveroline is a dopamine-derived neurotoxin candidate associated with the pathogenesis of Parkinson's disease ^[3]. Papaveroline can be used in the research of Alzheimer's disease and Parkinson's disease ^[3].

In Vitro, Papaveroline inhibits rat brain microsomal Na+,K+-ATPase with an IC₅₀ of 0.20 mM and inhibits rat brain microsomal Mg2+-ATPase with an I50 of 0.40 mM^[2]. Papaveroline inhibits rat brain microsomal K+-activated pNPPase with an IC₅₀ of 1.51 mM, which is less potent than its inhibition of rat brain microsomal Na+,K+-ATPase^[2]. Papaveroline (75-100% inhibition; 10 min)-mediated inhibition of rat brain microsomal Na+,K+-ATPase is freely reversible, as enzyme activity returns to control levels following washing and resuspension of the enzyme^[2]. Papaveroline (200-400 μM) acts as a simple linear noncompetitive inhibitor of rat brain microsomal Na+,K+-ATPase with respect to ATP, exhibiting an apparent Ki of 380.00 μM^[2]. Papaveroline (300 μM) decreases the apparent affinity of rat brain microsomal Na+,K+-ATPase for Na+ by increasing the K0.5 by 65% without altering cooperative binding at the Na+ site or the enzyme's Vmax^[2]. Papaveroline inhibits beef cardiac Na+,K+-ATPase with an IC₅₀ of 0.76 mM, which is less potent than its inhibition of rat brain microsomal Na+,K+-ATPase^[2]. Papaveroline (100-500 μM; 18 h) induces apoptosis in the majority of human dopaminergic neuroblastoma SH-SY5Y cells at 100 μM and 250 μM (69.19% and 83.07% apoptotic cells, respectively) and shifts to mostly necrosis at 500 μM (67.88% necrotic cells)^[3]. Papaveroline (250 μM; 3 h) does not significantly reduce intracellular ATP levels in human dopaminergic neuroblastoma SH-SY5Y cells, with a measured concentration of 4.79 nmol/mg protein after 3 h incubation^[3].

References:
[1]. Bhat SS, et al. Computational Insights into Papaveroline as an In Silico Drug Candidate for Alzheimer's Disease via Fyn Tyrosine Kinase Inhibition. Molecular biotechnology. 2025 Jul;67(7):2743-2757.
[2]. Meyerson LR, et al. Isoquinoline alkaloids. Inhibitory actions on cation-dependent ATP-phosphohydrolases. Neurochemical research. 1978 Apr;3(2):239-57.
[3]. Maruyama W, et al. Dopaminergic neurotoxins, 6,7-dihydroxy-1-(3', 4'-dihydroxybenzyl)-isoquinolines, cause different types of cell death in SH-SY5Y cells: apoptosis was induced by oxidized papaverolines and necrosis by reduced tetrahydropapaverolines. Neuroscience letters. 2000 Sep 15;291(2):89-92.