B1 receptor antagonists: different binding different biological effect; engagement of N114 in the allosteric minor pocket promotes receptor internalization
Il 11/10/2019 ore 12.00 - 13.00
Sala Conferenze Cnr, Area della Ricerca Na1, via Pietro Castellino 111, 80131 Napoli
Dr. Carmine Talarico (Dompé Pharmaceutici SpA, Napoli) will give a seminar on 'B1 receptor antagonists: different binding different biological effect; engagement of N114 in the allosteric minor pocket promotes receptor internalization'.
The kallikrenin-kinin system comprised kininogen precursor, kallikrenin proteolytic enzymes, kinin peptides and two G-protein coupled receptor B1 and B2 that transduce the kinins biological effects. The therapeutic potential of both promoting and inhibiting the function of kinins has been explored, in fact it turned out that angiotensin-converting enzyme (ACE) inhibitors, the most known drug class for cardiovascular area, also impaired bradykinin degradation pathway. Conversely, B1 and B1 inhibition proved to be pivotal in controlling chronic pain and inflammation. Particularly, B1 receptor proved to be involved in the chronic phase of pain and inflammation processes being quite absent in physiological condition while it is strongly up-regulated upon injuries. B1 receptor recruits similar signaling pathways than B2 but it is poorly sensitive to desensitization. Industry drug discovery interest for B1 antagonists for analgesic development reached a peak in … but almost all promising molecules failed in clinical trials. Little is known about these molecules mechanism of action and additional information will be necessary for the B1 receptor potential as target in painful pathologies as …. Here we reported the discovery by chemical libraries design and in silico screening of a new allosteric B1 antagonist, moreover its pharmacological characterization, in comparison with another allosteric compound and the peptidic orthosteric inhibitor [Leu8]-Lys-desArg9-BK, highlighted different effects of the binding mode on activity, receptor occupancy and internalization of B1 receptor. The elucidating of the differences in the biological behavior of similar compounds with the same binding site, can help in the design of new B1-targeting successful drugs.
Organizzato da:
Cnr - Istituto di Biochimica e Biologia Cellulare
Referente organizzativo:
Andrea Beccari
Dompè Pharmaceutici
c/o Istituto di biochimica e biologia cellulare, Cnr, via Pietro Castellino 111, 80131 Napoli
andrea.beccari@dompe.com
081 6132339
Modalità di accesso: ingresso libero
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