SINTESI E ATTIVITA’ BIOLOGICA DILIGANDI DEL RECETTORE OPPIOIDE DOP
2009
The opioid system, constituted by MOP, DOP and KOP receptors, modulates different
physiological functions.
Most of the terapeutical drugs are able to interact with MOP and KOP receptors and are
used as analgesics. Recent scientific papers suggest the use of DOP agonists as
antidepressive, with a different way of action compared to drugs actually used in
therapy for this pathology. On the contrary, molecules with DOP antagonist activity are
able to retard tollerance development, inevitable phenomenon associated with the use of
classical MOP ligands, such as morphine. This data suggest an association between
DOP antagonists and MOP agonists for the antidolorific therapy or the develop of new
drugs able to activate MOP receptors and, at the same time, to exercise the one
occupation of DOP receptors (MOP agonists / DOP antagonists). This pharmacological
profile could be the aim of a new class of analgesics for the chronic pain therapy.
In this thesis project two new classes of opioid ligands have being developed. They are
characterized by the DOP selective pharmacophore Dmt-Tic. First of all, modification
of the amidic spacer between Dmt-Tic and a second pharmacophore with an olefinic
spacer of variable lenght has produced molecules with DOP affinity and different
pharmacological activities (agonist, partial agonist, antagonist or inverse agonist). Their
chemical and physical characteristics confer to the molecules a greater lipofilicity and a
major metabolic stability, those physicochemical properties are necessary to carry out
animals chronic studies. Secondly, Dmt-Tic C-terminal funtionalization with ortosubstituted
anilides has generally produced molecules with DOP and MOP high affinity
except compound (123), characterized by a carbossilic moiety, that has revealed an
elevated DOP selectivity.
Lastly, a new cheap synthetic way has been developed for the preparation of L-Dmt
amminoacid in a multigram scale.
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