SINTESI E ATTIVITA’ BIOLOGICA DI LIGANDI DEL RECETTORE OPPIOIDE DOP

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.