Allelochemical activities of pyrrolizidine alkaloids: Interactions with neuroreceptors and acetylcholine related enzymes

Thirteen pyrrolizidine alkaloids (PAs) 3'-acetylheliosupine, echihumiline, echihumiline N-oxide, echimidine, heliosupine, heliosupine N-oxide, heliotrine, monocrotaline, pycnanthine, retronecine, riddeline, senecionine, and seneciphylline) were analyzed for their interactions with acetylcholine-related enzymes, such as acetylcholine esterase (AChE), butyrylcholinesterase (BChE), choline acetyl transferase (ChAT), and neuroreceptors, such as alpha(1)- and alpha(2)-adrenergic, nicotinergic (nACh), muscarinergic (mACh) and serotonin(2) (5-HT2) receptors. Whereas most PAs did not affect the enzymes, they show significant binding activities to mACh and 5-HT2 receptors: Twelve PAs exhibited a 50\% inhibition of the specific binding of the radioligand {[}H-3]quinuclidinyl benzilate (QNB) at the mAChR, i.e., IC50 values were between 8.7 mu M and 512.5 mu M, and 10 PAs exerted a 50\% inhibition of the specific binding of the radioligand {[}H-3]ketanserine at the 5-HT(2)R with IC50 values between 23.2 mu M and 608.6 mu M. The most active compound was 3'-acetylheliosupine, which was able to bind to all of the studied receptors with IC50 values in the range between 2.9 mu M and 159.7 mu M. The data imply that free PAs and PA N-oxides can affect several molecular targets: Besides longterm toxicity through DNA alkylation (by PA metabolites generated in the liver), liver and pneumotoxicity, neuroreceptors (among other molecular targets) may be modulated. The interference of PAs with neuronal signal transduction could mediate adverse physiological responses in herbivores and could thus contribute to chemical defense in plants and animals against herbivores and predators.