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VOL. 73 (2), 537-566, 2007 ECTO-NUCLEOTIDASES, MOLECULAR PROPERTIES...

compounds that have been reported to inhibit hydrolysis of ATP
without significantly acting on purinoceptors are the structural
analogues of ATP, ARL 67156 (FPL 67156) (6-N,N-diethyl-D-ß,?-
dibromomethylene ATP) (104-106) and 8-thiobutyladenosine 5’-
triphosphate (8-BuS-ATP) (107) and 1-naphthol-3, 6-disulfonic acid
(BG0136) (103). Recently, high throughput assay systems for ecto-
nucleotidase analysis have been developed and polyoxometalates
have been implicated as a new class of very potent NTPDase
inhibitors (108, 109). These substances can be applied systemically
and hold promise to finally provide a pharmacological access to this
enzyme family. Importantly, the potency of these and other inhibitors
can vary considerably between individual members of the E-NTPDase
family (109-111). This opens the possibility of isoform-specific ecto-
nucleotidase targeting.

Similarly, the hydrolysis of ApnAs by NPP1 to NPP3 is
differentially inhibited by P2 receptor antagonists. Thus, the
application of P2 receptor inhibitors will potentially obscure
pharmacological experiments in which the effects of ApnAs on P2
receptors are investigated. ApnA hydrolysis and P2 receptors would
be simultaneously blocked. In addition, submilligram quantities of
heparin or heparan sulphate inhibit activity of NPPs in a variety
of cellular systems (71). Inhibition of alkaline phosphatase equally
varies between isoforms. TNAP is particularly sensitive to levamisole
and L-homoraginine. The other isoforms are sensitive to L-
phenylalanine (112). Ecto-5’-nucleotidase is inhibited by ATP and
ADP and by the non-hydrolyzable ADP analogue a,ß-methylene
adenosine 5’-diphosphate (AOPCP) (51). Several NAD+ analogues
have been employed as inhibitors of CD38 (113) and P1P5-di
(adenosine-5') pentaphosphate (Ap5A) is a potent inhibitor of
adenylate kinase, inclusive its surface-located form (76).

ECTO-NUCLEOTIDASES IN THE NERVOUS SYSTEM

Since both nucleotides and nucleosides contribute to signaling
between neurons and also between glial cells and glia and neurons
(114, 115) it is expected that ecto-nucleotidases play an important
role in modulating and controlling these signaling pathways.

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