ALLELOCHEMICAL ACTIVITIES OF PYRROLIZIDINE ALKALOIDS - INTERACTIONS WITH NEURORECEPTORS AND ACETYLCHOLINE RELATED ENZYMES

Thirteen pyrrolizidine alkaloids (PAs) 3'-acetylheliosupine, echihumil ine, echihumiline N-oxide, echimidine, heliosupine, heliosupine N-oxid e, heliotrine, monocrotaline, pycnanthine, retronecine, riddeline, sen ecionine, and seneciphylline) were analyzed for their interactions wit h acetylcholine-related enzymes, such as acetylcholine esterase (AChE) , butyrylcholinesterase (BChE), choline acetyl transferase (ChAT), and neuroreceptors, such as alpha(1)- and alpha(2)-adrenergic, nicotinerg ic (nACh), muscarinergic (mACh) and serotonin(2) (5-HT2) receptors. Wh ereas most PAs did not affect the enzymes, they show significant bindi ng activities to mACh and 5-HT2 receptors: Twelve PAs exhibited a 50% inhibition of the specific binding of the radioligand [H-3]quinuclidin yl 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 re ceptors 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 molec ular targets: Besides longterm toxicity through DNA alkylation (by PA metabolites generated in the liver), liver and pneumotoxicity, neurore ceptors (among other molecular targets) may be modulated. The interfer ence of PAs with neuronal signal transduction could mediate adverse ph ysiological responses in herbivores and could thus contribute to chemi cal defense in plants and animals against herbivores and predators.