title: Pharmacological and biochemical profiles of unique neurotensin 8-13 analogs exhibiting species selectivity, stereoselectivity, and superagonism.
abstract: Recently, the rat neurotensin receptor and the two human neurotensin receptor clones (differing by one amino acid residue) have been isolated. We present results with 33 newly synthesized neurotensin analogs. We have evaluated their binding potency at the three neurotensin receptor clones by determining equilibrium dissociation constants and coupling to phosphatidylinositol turnover. Our work focused on position 8 and 9 substitutions as well as position 11 of the neurotensin hexamer NT8-13. The results presented include: 1) the development of a compound that is species selective, with a binding potency at the rat receptor that is 20-fold more potent than at the human receptor; 2) the development of a pair of stereoselective compounds with the L-isomer exhibiting 190-700-fold more potency than the D-isomer; and 3) the development of an agonist that has a Kd of 0.3 and 0.2 nM at the human and rat neurotensin receptor, respectively, ranking it as among the most potent tested. Also, we present the first evidence that 1) the effect of pi electrons at position 11 (L-Tyr) are important for binding to the neurotensin receptor, and 2) the length of the side chain on position 9 (L-Arg) changes binding potency.
authors.affiliation: Mayo Foundation for Medical Education and Research, Jacksonville, Florida 32224, USA.
authors.forename: B
authors.initials: B
authors.lastname: Cusack
authors.forename: D J
authors.initials: DJ
authors.lastname: McCormick
authors.forename: Y P
authors.initials: YP
authors.lastname: Pang
authors.forename: T
authors.initials: T
authors.lastname: Souder
authors.forename: R
authors.initials: R
authors.lastname: Garcia
authors.forename: A
authors.initials: A
authors.lastname: Fauq
authors.forename: E
authors.initials: E
authors.lastname: Richelson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000737:chemistry; D010716:Phosphatidylinositols / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D018028:Receptors, Neurotensin / Q000819:agonists*; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010716:Phosphatidylinositols; D018028:Receptors, Neurotensin; D009496:Neurotensin