Neurotensin(8–13): Comparison of novel analogs for stimulation of cyclic GMP formation in neuroblastoma clone N1E-115 and receptor binding to human brain and intact N1E-115 cells

Abstract

Neurotensin(8–13), the carboxyl-terminal portion of neurotensin, is 4–50 times more potent than native neurotensin in binding to intact neuroblastoma N1E-115 cells and human brain tissue and in stimulation of intracellular cyclic GMP production and inositol phospholipid hydrolysis in clone N1E-115 (Gilbert JA and Richelson E, Eur J Pharmacol 99: 245–246, 1984; Gilbert JA et al., Biochem Pharmacol 35: 391–397, 1986; Kanba KS et al., J Neurochem 46: 946–952, 1986; and Kanba KS and Richelson E, Biochem Pharmacol 36: 869–874, 1987). A series of novel analogs of neurotensin (8–13) was synthesized, and a structure-activity study was done comparing the abilities of these peptides to stimulate intracellular cyclic GMP production in intact neuroblastoma clone N1E-115 and to inhibit the binding of [ 3H]neurotensin to these cells and to membranal preparations from human brain. A direct correlation was found for each analog between its EC 50 , for biochemical activity and its K D for binding ability in studies with clone N1E-115. Furthermore, a strong correlation existed for each peptide between its K D for binding to neurotensin receptors on these cells and its K D for binding to neurotensin receptors in human brain tissue. In this study, the residues that were important to the biochemical and binding activities of neurotensin (8–13) proved to be identical to the amino acids that are necessary for the functional integrity of native neurotensin (Gilbert JA et al., Biochem Pharmacol 35: 391–397, 1986).