Neurotensin Analogues
Journal of Medicinal Chemistry, 1977, Vol. 20, No. 11 1409
Neurotensin Analogues. Structure-Activity Relationships Jean E. Rivier,' Lawrence H. Lazarus, Marilyn H. Perrin, and Marvin R. Brown Laboratories for Neuroendocrinology, The Salk Institute for Biological Sciences, La Jolla, California 92037. Received April 18, 1977 A series of neurotensin (NT) analogues in which each amino acid has been successively replaced by its D isomer, as well as analogues involving modifications at positions 3 and 11 and a cyclic compound [ C ~ S * , ' ~ ] - Nhas T , been synthesized by solid-phase methodology. After purification by conventional techniques the compounds were characterized by thin-layer chromatography, amino acid analysis, and optical rotation. Further characterization of the analogues by high-pressure liquid chromatography demonstrates the high resolving power of this new method. Each analogue was studied for its ability to induce hypothermia in cold-exposed rats (4 "C) in vivo and to bind to mast cells in vitro. Although close correlation in potencies was not found for all the analogues tested in both assay systems, they substantiate the basic observation that substitutions in positions 1-9 produced active peptides whereas modification of residues 10-13 considerably decreased biological response in vitro and in vivo. One exception is the higher potency of [~-Phell]-NTand [~-Tyr'll-NTin vivo. The differences between the efficacies of these analogues in vivo and in vitro are discussed. Table I. Relative Potency Values of NT and NT Neurotensin (NT)I is a tridecapeptide whose sequence Analogues to Lower Body Temperature of Cold-Exposed is pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile(4 " C ) Rats or to Bind Specifically t o Mast Cells Leu-OH. It was originally isolated and characterized from Binding bovine hypothalamus.z Recent studies have demonstrated affinity N T or NT-like activity in canine, bovine, porcine, and Potency t o mast human gut.34 NT has a wide spectrum of pharmacologic re1 cells re1 actions including production of hypotension, gut conNo. Compd to NTa to NTb traction, increased vascular permeability, hemoconcenNeurotensin (NT) 1 100 1 0 0 tration, hyperglycemia, and hyperglucag~nemia.~~~~~~-~ NT [~-pGlul]-NT 100 120 2 also stimulates the secretion of growth hormone and [ D-Leu 1-NT 25 0 3 120 prolactin by a brain-dependent mechanism.10 Of con[o-Tyr3]-NT 4 200 60 siderable interest has been the recent observation that NT [D - G ~ u ~ I - N T 100 5 300 [ D - A s ~1-NT ' induces hypothermia after its intracisternal administration 100 6 100 [ D - L Y S1-NT ~ 7 110 100 to cold-exposed mice o r rats."Jz Since NT has been [D-Pro']-NT 100 8 100 demonstrated to be distributed throughout the central I D -Arg' 1-NT 9 100 500 nervous system with high levels in the h y p o t h a l a m u ~ , ' ~ - ~ ~ [ DArg91-NT 10 50 640 the hypothermic actions of this peptide may suggest that [ D-PrO' ']-NT 11
