CONFORMATIONALLY CONSTRAINED CCK8 ANALOGUES AS LIGANDS FOR CHOLECYSTOKININ RECEPTORS

摘要

Small radiolabeled compounds such as peptides are very attractive tools for the diagnosis of several different pathologies. Among the possible biological targets for radiolabeled compounds, the cholecystokinin receptors CCK_A-R and CCK_B-R are very promising, due to their overexpression in many tumours: CCKA-R is overexpressed in pancreatic cancer, while CCK_B-R is found in small cell lung cancer, colon and gastric cancers, medullary thyroid carcinomas, astrocitomas and stromal ovarian tumors. These receptors belong to the GPCR superfamily and are localized in the cell membrane. Both CCK_A-R and CCK_B-R have been thoroughly investigated with the aim of characterising the molecular basis of their interaction with the CCK peptide hormone. The NMR structures of two complexes formed by the natural ligand CCK8 with the N-terminal fragment of CCKA receptor and with the third extracellular loop (EL3) of CCKB receptor have been recently published. We used these structures as a starting point to design receptor selective CCK8 analogues.