Neurotensin (NT) is a tridecapeptide that participates in regulation of dopaminergic pathways implicated in nicotine addiction1.
NT belongs to a family of regulatory peptides that also includes neuromedin N (NMN), xenopsin, xenin, and the NT-related hexapeptide LANT-6. in rat 2.
NT was discovered by Carraway and Leeman in 1973. The stimulatory effects of NT and several NT fragments were evaluated by Quirion et al., in 1980, in pharmacological preparations of rat stomach strips and isolated spontaneously beating atria of guinea pigs 3.
Neurotensin (pGlu-L-Y-E-N-K-P-R-R-P-Y-I-L-OH, NT) is a regulatory peptide found in the brain and gut. Both rat stomach strips and cimetidine-treated atria of guinea-pigs were found suitable for studying the relationship between the chemical structure of NT and its myotropic or inotropic activity. Besides their relatively high sensitivity to NT, the two preparations allowed the measurement of at least two complete dose-response curves to NT or its fragments. Using both assays to evaluate the biological activities of NT and NT fragments, the following conclusions were drawn:
(a) The minimum structure required to produce the maximum response in the two preparations is
(b) The sequence 1-8 and the amino acids Ile12 and Leu13 contribute mainly to the affinity or binding of NT to its receptors;
(c) The sequence 9-11 (Arg9-Pro10-Tyr11) appears to contain the chemical groups responsible for the intrinsic activity or ability of NT to stimulate its receptors; 3
Structure-activity relationship studies by another group have shown that the C-terminal sequence [R-R-P-Y-I-L-OH, NT (8-13)] is sufficient in preserving high affinity receptor binding. Unfortunately, this truncated peptide has poor in vitro and in vivo serum stability. One site of enzymatic instability is the Arg8-Arg9 bond. By replacing one or both of the arginines with a suitable mimic, neurotensin analogs with increased serum stability have been prepared. They also found that the C-terminal region of the peptide is susceptible to degradation 4.
Cyclic analogues of NT: [cyclo (13----8), Gly8]NT-(8-13), [cyclo (13----7), Gly7]NT-(7-13), [cyclo (13----5 epsilon), Lys5]NT-(5-13), [cyclo (13----4 epsilon), Lys4]NT-(4-13), and their linear precursors have been synthesized by Grinshteine et al., in 1985. The latter (protected linear compounds) were prepared by solid-phase peptide synthesis, and cyclization was attained by using diphenylphosphoryl azide. Cyclization of C-terminal hexa- and octapeptide fragments of NT was found to lead to cycloanalogues possessing high depressor activity. As judged by CD spectral data in aqueous solution, the cyclohexapeptide analogue has a relatively rigid conformation different from its linear counter-part and the NT-(9-13) fragment, whereas NT, its cyclohepta- and cyclononapeptides have random structure 5.
Mode of Action
In mammals, NT and related peptides exert their biological effects through three distinct types of receptors termed NT receptor type (NTR) 1, NTR2, and NTR3. NTR1 and NTR2 belong to the family of seven-transmembrane domain G protein-coupled receptors, whereas NTR3 is a single-transmembrane domain non-G protein-coupled receptor. All types of NT receptors are able to bind the C-terminal region of NT, NT8–13, which is the shortest biological active fragment of the peptide. The three NT receptors are expressed in the central nervous system and in peripheral organs. For instance, NTR1 mRNA is expressed in the gastrointestinal tract, NTR2 mRNA is present in the uterus and gastric fundus, and NTR3 mRNA is found in the spinal cord, heart, thyroid, placenta, and testis 2.
NTR are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity synthesized by replacing arginine residues with lysine and arginine derivatives, were used to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer 6.
The N-terminal NT fragment NT1–11 inhibits cortisol secretion, whereas NT, NT1- 8 and NT8–13 are devoid of effect on corticosteroidogenesis. This observation indicates that, besides its intrinsic inhibitory effect, NT1–11 may also modulate the responses of the human adrenal gland to corticotropic factors. The data suggests that NT1–11 itself or synthetic NT1–11 agonists may be of potential interest for the treatment of both Adrenocorticotropic hormone (ACTH) independent and -dependent hypercortisolisms 2.
NT and its active fragment NT (8-13) elicit behavioral responses typical of clinically used antipsychotic drugs when administered directly to the brain. However, limited peptide stability and oral bioavailability have prevented these compounds from being developed as relevant pharmaceuticals. Recently a first-generation NT (8-13) derivative, KK13, was designed. This derivative elicited key pharmacokinetic and behavioral responses typical of clinically used antipsychotic drugs when administered to rats parenterally. This compound was the basis for the rational design of a series of second-generation NT (8-13) analogs (KH1-KH30). Initial screening of these analogs for central nervous system activity by monitoring hypothermia induction after peripheral administration defined several compounds (KH11, KH24, KH26, and KH28-KH30) that warranted further investigation. Each compound maintained binding affinity for NTR (1), however, only KH24, KH26, and KH28 (as well as KK13) elicited significant hypothermic responses after oral administration. Of these, KH28 demonstrated an oral activity 3-fold greater than any other analog; hence it was further characterized in a series of rat behavioral assays. KH28 attenuated d-amphetamine induced hyper-locomotion. In addition, tolerance to the compound did not develop after repeated daily dosing, as measured by hypothermic induction as well as attenuation of d-amphetamine induced hyper-locomotion. Finally, KH28 did not produce catalepsy, a deleterious side-effect elicited by classical antipsychotic drugs. KH28 is considered to be an ideal compound for further development as a potential novel antipsychotic 7.
A brain-penetrating neurotensin analog, NT69L, blocks nicotine-induced locomotor sensitization by blocking both the initiation and the expression of sensitization. In addition, chronic NT69L administration blocked the acute effects of nicotine on norepinephrine and serotonin in prefrontal cortex 1.
1. Fredrickson P, Boules M, Yerbury S, Richelson E (2003). Novel neurotensin analog blocks the initiation and expression of nicotine-induced locomotor sensitization. Brain Res., 979(1-2):245-248.
2. Sicard F, Contesse V, Lefebvre H, Ait-Ali D, Gras M, Cartier D, Decker A, Chartrel N, Anouar Y, Vaudry H, Delarue C. (2006). The N-Terminal Neurotensin Fragment, NT1–11, Inhibits Cortisol Secretion by Human Adrenocortical Cells. J Clin Endocrinol Metab., 91(8):3131–3137.
3. Quirion R, Regoli D, Rioux F, St-Pierre S (1980). The stimulatory effects of Neurotensin and related peptides in rat stomach strips and guinea pig atria. Br. J. Pharmac., 68:83-91
4. Michelle A. Schmidt MA, Jack L. Erion JL, Lori K. Chinen LK, Joseph E. Bugaj JE, R. Randy Wilhelm RR, and Ananth Srinivasan A (2006). Increased serum stability of neurotensin analogs containing arginine mimics. Peptides for the New Millennium., 6: 634
5. Grinshteine IV, Myshliakova NV, Vegner RE, Vosekalna IA, Gailite EA (1985). [Synthesis and study of cyclic and linear analogs of neurotensin]. Bioorg Khim., 11(12):1589-1597.
6. Janssen PJ, de Visser M, Verwijnen SM, Bernard BF, Srinivasan A, Erion JL, Breeman WA, Vulto AG, Krenning EP, de Jong M (2007). Five Stabilized 111In-labeled neurotensin analogs in nude mice bearing HT29 tumors. Cancer biother radiopharm., 22(3):374-381.
7. Hadden MK, Orwig KS, Kokko KP, Mazella J, Dix TA (2005). Design, synthesis, and evaluation of the antipsychotic potential of orally bioavailable neurotensin (8-13) analogues containing non-natural arginine and lysine residues. Neuropharmacology, 49 (8):1149-1159.
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