Page 94 - 73_02

HERBERT ZIMMERMANN Y COLS. AN. R. ACAD. NAC. FARM.

the formation of extracellular adenosine from extracellular nucleotide
in several tissue functions (96). Deletion of CD38 underlined the role
of the protein in regulating the humoral immune response (97) but
also revealed its participation in osteoclast formation and bone
resorption (98). Similarly, deletion of CD157 implicates a role in B cell
development and antibody production (99).

From these and from many additional studies it has become
evident that ecto-nucleotidases are involved in the control of a large
variety of physiological and pathophysiological functions mediated
by nucleotides (41-44, 50, 96, 100, 101). Examples include epithelial
ion and fluid transport (5’-nucleotidase), tissue barrier functions such
as the transmigration of leucocytes through the vascular endothelium
(5’-nucleotidase; CD38), blood flow, including platelet aggregation
and ischemia and reperfusion (5’-nucleotidase, NTPDase1),
angiogenesis and vascular remodeling (NTPDase1), renal function
(5’-nucleotidase), hypoxia (5’-nucleotidase, NTPDase1), the immune
system (CD38, NPP1, NTPDase1, 5’-nucleotidase), the function of
airway epithelia including chronic lung disease (NPPs, NTPDases,
alkaline phosphatase, ecto-adenylate kinase, ecto-5’-nucleotidase) or
bone and cartilage mineralization (NPP1, TNAP). In the nervous
system, ecto-nucleotidases have been implicated in a considerable
variety of functions, including synaptic signal transmission,
microglial function and neurogenesis. There is increasing evidence
for an involvement of ecto-nucleotidases in sensory transmission as
for example for NTPDase1 to NTPDase3 in the inner ear (102).

INHIBITORS OF ECTO-NUCLEOTIDASES

Inhibition of ecto-nucleotidases represents an important mode to
target nucleotide signaling pathways. Obviously, targeting ecto-
nucleotidases will affect not only nucleotide signaling per se but also
additional cooperative or opposing signaling pathways. Ideally, ecto-
nucleotidase inhibitors should neither be P2 or P1 receptor agonists
or antagonists nor substrates of ecto-nucleotidases (60, 103).

Inhibitors of NTPDases (Table 1) include non-hydrolyzable
nucleotide analogues and P2 receptor antagonists. Among the

552