The anti-schistosomal drug praziquantel is an adenosine antagonist.
The mechanism of action of praziquantel (PZQ), the drug of choice against schistosomiasis, is still unclear. Since exposure of schistosomes to the drug is associated with calcium influx and muscular contraction, calcium channels have been suggested as the target, although direct combination of PZQ with their subunits was never demonstrated. We report a hitherto unknown effect of PZQ, namely the inhibition of nucleoside uptake, as observed in living worms using radio-isotope labelled adenosine and uridine. This effect is clearly seen in schistosomes but is absent in mammalian cells in culture. Moreover it is a specific pharmacological effect seen exclusively with the active levo-R(-)stereo isomer of the drug, and is shared by at least one benzodiazepine having antischistosomal activity. This novel effect acquires significance given that schistosomes cannot synthesize purine nucleosides de novo. A possible relationship between this novel effect and the known action of PZQ on calcium channels is discussed, since adenosine is known to bind to specific receptors and to behave as an indirect antagonist of calcium release in mammalian cells. If calcium channels were correlated with adenosine receptors also in schistosomes, as they are in mammals, this would support the hypothesis that PZQ-induced calcium influx may be correlated to adenosine receptor blockade.
Angelucci
F
F
Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto Pasteur - Fondazione Cenci Bolognetti, Università di Roma Sapienza, Piazzale Aldo Moro 5, 00185 Roma, Italy.
Basso
A
A
Bellelli
A
A
Brunori
M
M
Pica Mattoccia
L
L
Valle
C
C
D000241:Adenosine / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001700:Biomphalaria / Q000469:parasitology; D008715:Methionine / Q000494:pharmacology; D015394:Molecular Structure; D009543:Nifedipine / Q000494:pharmacology; D011223:Praziquantel / Q000737:chemistry / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D012550:Schistosoma mansoni / Q000187:drug effects; D012556:Schistosomicides / Q000494:pharmacology*; D002998:Clonazepam / Q000031:analogs & derivatives
D000241:Adenosine; D001569:Benzodiazepines; D001570:Benzodiazepinones; D008715:Methionine; D009543:Nifedipine; D011223:Praziquantel; D058915:Purinergic P1 Receptor Antagonists; D012556:Schistosomicides; C020602:meclonazepam; D002998:Clonazepam