Biology Reference
In-Depth Information
PDE isoenzymes (Thompson and Appleman
1971
). Thompson and his associates
separated PDEs from cardiac and cerebellum tissues (Thompson et al.
1979
), and
Hidaka and Polson resolved those of platelets and canine trachea (Hidaka and
Asano
1976
; Polson et al.
1982
). Platelets and cardiac tissue each revealed three
peaks of PDE activity, whereas in canine trachea five different peaks of PDE
activity were resolved. The PDEs in each of the peaks were characterised with
enzymologic criteria such as (1) substrate specificity (cAMP/cGMP), (2) substrate
affinity and (3) calmodulin and cGMP activation, but the data were hardly compa-
rable and, even worse, every author used his own nomenclature. The discrimination
of five different PDE classes emerged only after the separation methods were more
refined and more selective tools (activators/inhibitors) were applied for character-
isation of the peaks. Much of the confusion concerning the PDEs was largely ended,
and each PDE peak of tissue-specific elution pattern could be attributed to this
system. However, other complications such as proteolysis and expression of
myriads of alternative splice variants in some families continued to complicate
understanding of these enzymes. The publication of Reeves in 1987 (Reeves et al.
1987b
) clarified that the cardiac peak III can be further separated into two cAMP-
hydrolyzing PDEs where the earlier eluting peak is the highly cAMP specific
rolipram-sensitive (now known as PDE4) and the later eluting cGMP-inhibited
cAMP-PDE (now known as PDE3). This publication marks the time point when the
system of PDE1-PDE5 with their typical enzymological characteristics became
established in most laboratories that were engaged in PDE research (Weishaar et al.
1985
; Nicholson et al.
1989
; Schudt et al.
1991a
,
b
,
c
; Torphy and Cieslinsky
1989
).
The elegant concept of a protein superfamily of six PDE families with each family
containing several members was composed by Joe Beavo (
1988
), and many later
publications along with the contributions of other pioneers in the field (Marco Conti
and Rick Heaslip) unfolded the whole world of
60 PDEs in 11 families (Beavo
et al.
1994
; Conti and Beavo
2007
). The enormous biodiversity of these key
regulatory enzymes and the view of their distribution in different tissues underlined
the rationale for searching for new drugs with defined selectivity for one or more
PDE families or subtypes.
Around 1985, a pool of around 30 PDE inhibitors with weak potencies and
selectivities was available; these have been listed and their chemistry has been
described extensively in excellent reviews of that time (Weishaar et al.
1985
;
Torphy and Undem
1991
; Nicholson et al.
1991
; Beavo
1988
). Prominent repre-
sentatives and important tools for research progress at that time were SKF 94120,
SKF 94 836, milrinone and motapizone for PDE3, rolipram and Ro 20-1724 for
PDE4 and zaprinast for PDE5. Milrinone, rolipram and zaprinast had already been
studied in patients as cardiotonics, antidepressants and bronchodilators, respec-
tively (see Table
1
). Due to insufficient safety or low therapeutic efficacy, these
developments had to be discontinued. The positive aspects of these early and
engaged trials was the demonstration that therapeutic efficacy in principle is
possible and can be improved. Further, the recognition of AEs and of the necessity
to study and understand their biochemical mechanisms was of considerable value
for future research (for details of rolipram studies, see following chapters). On the
>
