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VOL. 73 (3), 703-746, 2007 ARE ADRENOMEDULLIN POSITIVE MODULATORS NOVEL...

and peptides of the extracellular medium as mentioned before.
Adrenomedullin (AM), a 52 amino acid peptide isolated from a
human pheochromocytoma (adrenal tumour) (21), is an interesting
example of MMP substrate. Martínez et al., have reported how the
adrenomedullin is cleaved by MMP-2 (1). Interestingly they also
report that AM is not cleaved by MMP-9, so MMP-2 may be
considerered as a specific protease of AM.

Our group has identified by a HTS a series of compounds that
modulate the activity of adrenomedullin (Table 2) (22). These
compounds have demonstrated to increase the production of cAMP,
the second messenger released upon binding of AM to its receptor,
but, interestingly, only in presence of the AM peptide. Furthermore,
they are able to bind to AM but there is no direct relationship between
the affinity to AM and the amount of cAMP production. These facts
led us to the hypothesis that the mechanism of action of these
compounds may involve affecting the availability of AM. That is,
modulators of AM could inhibit the MMP-2 protease activity, so, the
AM levels would be increased and consequently the cAMP production
would be elevated. This work tries to shed light into the possibility
that AM modulators and some derivatives could act as matrix
metalloproteinases inhibitors. This hypothesis could drive, not only
to an explanation of the mechanism of action of the modulators, but
also to the discovery of novel ZBGs which could be exploited for the
design of potent and selective inhibitors for MMP-2.

TABLE 2. Positive AM modulators and related compounds, that were used in the
computational study

Series 1 Series 2 Series 3
compd n R’ compd
R n compd N

1a 8 Ph NH-Ph 2j 4 3j 4
5 3k 5
1b 8 p-Cl-phenyl NH2 2k

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