Neurotensin Receptor Binding Research Articles

Imaging Neurotensin Receptor in Prostate Cancer With 64Cu-Labeled Neurotensin Analogs.

Introduction:Neurotensin receptor 1 (NTR-1) is expressed and activated in prostate cancer cells. In this study, we explore the NTR expression in normal mouse tissues and study the positron emission tomography (PET) imaging of NTR in prostate cancer models.Materials and Methods:Three 64Cu chelators (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid [DOTA], 1,4,7-triazacyclononane-N,N′,N″-triacetic acid [NOTA], or AmBaSar) were conjugated to an NT analog. Neurotensin receptor binding affinity was evaluated using cell binding assay. The imaging profile of radiolabeled probes was compared in well-established NTR+ HT-29 tumor model. Stability of the probes was tested. The selected agents were further evaluated in human prostate cancer PC3 xenografts.Results:All 3 NT conjugates retained the majority of NTR binding affinity. In HT-29 tumor, all agents demonstrated prominent tumor uptake. Although comparable stability was observed, 64Cu-NOTA-NT and 64Cu-AmBaSar-NT demonstrated improved tumor to background contrast compared with 64Cu-DOTA-NT. Positron emission tomography/computed tomography imaging of the NTR expression in PC-3 xenografts showed high tumor uptake of the probes, correlating with the in vitro Western blot results. Blocking experiments further confirmed receptor specificity.Conclusions:Our results demonstrated that 64Cu-labeled neurotensin analogs are promising imaging agents for NTR-positive tumors. These agents may help us identify NTR-positive lesions and predict which patients and individual tumors are likely to respond to novel interventions targeting NTR-1.

Identification and Functional Characterization of a Stable, Centrally Active Derivative of the Neurotensin (8−13) Fragment as a Potential First-in-Class Analgesic

The neurotensin hexapapetide fragment NT(8-13) is a potent analgesic when administered directly to the central nervous system but does not cross the blood-brain barrier. A total of 43 novel derivatives of NT(8-13) were evaluated, with one, ABS212 (1), being most active in four rat models of pain when administered peripherally. Compound 1 binds to human neurotensin receptors 1 and 2 with IC(50) of 10.6 and 54.2 nM, respectively, and tolerance to the compound in a rat pain model did not develop after 12 days of daily administration. When it was administered peripherally, serum levels and neurotensin receptor binding potency of 1 peaked within 5 min and returned to baseline within 90-120 min; however, analgesic activity remained near maximum for >240 min. This could be due to its metabolism into an active fragment; however, all 4- and 5-mer hydrolysis products were inactive. This pharmacokinetic/pharmacodynamic dichotomy is discussed. Compound 1 is a candidate for development as a first-in-class analgesic.

Protein kinase C inhibitors alter neurotensin receptor binding and function in prostate cancer PC3 cells

Prostate cancer PC3 cells expressed constitutive protein kinase C (PKC) activity that under basal conditions suppressed neurotensin (NT) receptor function. The endogenous PKC activity, assessed using a cell-based PKC substrate phosphorylation assay, was diminished by PKC inhibitors and enhanced by phorbol myristic acid (PMA). Accordingly, PKC inhibitors (staurosporine, Go-6976, Go-6983, Ro-318220, BIS-1, chelerythrine, rottlerin, quercetin) enhanced NT receptor binding and NT-induced inositol phosphate (IP) formation. In contrast, PMA inhibited these functions. The cells expressed conventional PKCs (α, βI) and novel PKCs (δ, ε), and the effects of PKC inhibitors on NT binding were blocked by PKC downregulation. The inhibition of NT binding by PMA was enhanced by okadaic acid and blocked by PKC inhibitors. However, when some PKC inhibitors (rottlerin, BIS-1, Ro-318220, Go-69830, quercetin) were used at higher concentrations (>2 μM), they had a different effect characterized by a dramatic increase in NT binding and an inhibition of NT-induced IP formation. The specificity of the agents implicated novel PKCs in this response and indeed, the inhibition of NT-induced IP formation was reproduced by PKCδ or PKCε knockdown. The inhibition of IP formation appeared to be specific to NT since it was not observed in response to bombesin. Scatchard analyses indicated that the PKC-directed agents modulated NT receptor affinity, not receptor number or receptor internalization. These findings suggest that PKC participates in heterologous regulation of NT receptor function by two mechanisms: a) — conventional PKCs inhibit NT receptor binding and signaling; and b) — novel PKCs maintain the ability of NT to stimulate PLC. Since NT can activate PKC upon binding to its receptor, it is possible that NT receptor is also subject to homologous regulation by PKC.

Neurotensin receptor binding and neurotensin-induced growth signaling in prostate cancer PC3 cells are sensitive to metabolic stress

Neurotensin (NT) stimulates the proliferation of prostate cancer PC3 cells, which express high levels of its G protein-coupled receptor NTS1. To shed light on mechanisms that might serve to coordinate mitogenic responses to metabolic status, we studied the effects of metabolic inhibitors on NTS1 function. We also related these effects to cellular ATP levels and to the activation of AMP-activated protein kinase (AMPK). Glycolytic and mitochondrial inhibitors, at concentrations that reduced cellular ATP levels, altered NT binding to the cells, inhibited NT-induced inositol phosphate formation, and inhibited NT-induced DNA synthesis. For eight of the nine inhibitors, the potencies to alter NT receptor function correlated to the potencies to decrease cellular ATP levels. In keeping with its known role to oppose metabolic stress, AMPK was activated by the metabolic inhibitors. Accordingly, the AMPK activator AICAR elevated cellular ATP levels and produced effects on NTS1 function that were opposite to those for the metabolic inhibitors. These results indicate that metabolic stress inhibited NTS1 function by a mechanism that involved a fall in cellular ATP levels and that was opposed by activation of AMPK. In a broader context, these findings are compatible with the idea that one means by which cells might coordinate mitogenic signaling to metabolic status could involve changes in growth factor receptor function.

Novel bioactive and stable neurotensin peptide analogues capable of delivering radiopharmaceuticals and molecular beacons to tumors.

The prevalence of neurotensin receptor (NTR) in several human tumors makes it an attractive target for the delivery of cytotoxic drugs and imaging agents. Native neurotensin (NT) is a tridecapeptide that binds to NTR and induces tumor growth. Unfortunately, NT has a short plasma half-life, which hinders its use for in vivo biomedical applications. Numerous reports suggest that Arg(8)-Arg(9) and Tyr(11)-Ile(12) amide bonds are particularly susceptible to degradation by proteolytic enzymes. Predicated on this observation, we substituted Arg(8), Arg(9), and Ile(12) amino acids with the corresponding commercially available mimics. These surrogate amino acids are amenable to standard Fmoc peptide synthesis strategy, and the resulting compounds are stable in biological media for >4 h and bind to NTR with high affinity. Furthermore, conjugating DTPA to the new peptides and subsequent labeling with (111)In-DTPA for nuclear imaging or fluorescein for optical imaging did not diminish the NTR binding affinities of the peptides. In vivo biodistribution of a representative (111)In-DTPA-NT peptide analogue in SCID mice bearing NTR-positive human adenocarcinoma (HT29) xenograft shows that the compound was primarily retained in tumor tissue (2.2% ID/g) and the kidneys (4.8% ID/g) at 4 h postinjection. Coinjection of cold NT and the radiolabeled NT peptide analogue inhibited the tumor but not the kidney uptake, demonstrating that retention of the radiolabeled compound in tumor tissue was mediated by NTR specific uptake while it accumulates in the kidneys by a nonspecific mechanism. These findings show that the new NT peptide analogues are robust and can deliver imaging agents to NTR-positive tumors such as pancreatic cancer.

Neurotensin receptor binding abnormalities in the entorhinal cortex in schizophrenia and affective disorders

Background: Convergent evidence from in vivo and in vitro studies of schizophrenia have implicated the mesial temporal lobe as a primary site of pathological change in this disorder. We have previously reported decreased neurotensin receptor density in layer II of the intermediate entorhinal cortex (ERC) in schizophrenia, a finding seen elsewhere but not seen in more caudal ERC. Methods: To study neuroanatomic and diagnostic specificity, we measured the density of neurotensin receptors in the intermediate and caudal ERC and hippocampal formation of schizophrenic, affective disorder control subjects, and normal control subjects. Slide-based radioligand binding was used to perform these studies. Results: Not only schizophrenic but also affective disorder subjects had decreased neurotensin receptor density in layer II of the intermediate ERC. Affective disorder subjects had significantly decreased neurotensin receptor density in layers V/VI of the intermediate ERC, and schizophrenic subjects trended in the same direction. Conclusions: These findings demonstrate region-specific changes in neurotensin receptor binding levels in the mesial temporal lobe; however, there is no clear diagnostic specificity for these changes, because they were seen to varying degrees in both schizophrenia and affective disorders.

Confirmation of Correlations and Common Quantitative Trait Loci Between Neurotensin Receptor Density and Hypnotic Sensitivity to Ethanol

In previous studies, genetic correlations were observed between hypnotic sensitivity to ethanol and high-affinity neurotensin receptor (NTS1) binding. Provisional quantitative trait loci (QTLs) were identified for these traits, and some of these QTLs were found on common chromosomal regions. In continued efforts to examine the relationship between NTS1 binding capacity and hypnotic sensitivity to ethanol, studies were designed to confirm correlations between NTS1 densities in the brain, duration of ethanol-induced loss of righting reflex (LORR), and blood ethanol concentrations at regain of righting reflex (BECRR). Another purpose of the study was to confirm QTLs for these traits. ILS X ISS F2 mice and HAS X LAS F2 rats as well as the progenitors were tested for LORR, BECRR, and NTS1 densities. Phenotypic correlations were calculated between LORR and BECRR and between these measures and NTS1 densities in striatum from both mice and rats. The F2 mice were genotyped by using polymorphic markers for five previously reported QTLs for LORR to confirm QTLs for BECRR and NTS1 densities in striatum, ventral midbrain, and frontal cortex. Phenotypic correlations were found between LORR and BECRR (r = -0.66 to -0.74, p < 10(-9)) and between these measures and NTS1 densities in striatum (r = 0.28-0.38, p < 10(-2)) from both mice and rats. QTLs for LORR and BECRR (lod score = 2-6) were found in common regions of chromosomes 1, 2, and 15. By using the combined results from a previous LSXSS RI study and the current results, a suggestive QTL (lod score = 3.1) for striatal NTS1 receptor densities was found on chromosome 15 at approximately 60 cM, in the same region as the chromosome 15 LORR/BECRR QTL. The results are in agreement with previously reported correlations and QTLs for NTS1 receptor densities and measures of hypnotic sensitivity to ethanol in mice and extend those correlations to another species, the rat. These findings support a role for NTS1 in genetically mediated differences in hypnotic sensitivity to ethanol.

Synthesis of neurotensin(9–13) analogues exhibiting enhanced human neurotensin receptor binding affinities

Recent evidence is consistent with neurotensin (NT)(8–13) adopting a Type I β-turn conformation while binding the NT receptor, which would place the cationic side-chains of Arg(8) and Arg(9) in close proximity. This was the basis for the design, synthesis and analysis of truncated NT(9–13) analogues 1– 5 with dicationic position 9 side-chains to emulate the functions of the 8 and 9 side-chains of NT(8–13).

Synthesis and human neurotensin receptor binding activities of neurotensin(8-13) analogues containing position 8 alpha-azido-N-alkylated derivatives of ornithine, lysine, and homolysine.

A series of neurotensin(8-13) (NT) analogues were synthesized through intermediates in which the N-terminal Arg(8) was replaced by various omega-bromo-2(S)-azido residues spanning 3-5 methylene units in side-chain length. Subsequent nucleophilic substitution of the omega-bromo groups with ammonia, methylamine, dimethylamine, or trimethylamine provided peptides containing N-terminal 2(S)-azido residues containing primary through quaternary N-alkylated side chains corresponding in length to ornithine, Lys, and homolysine. The synthetic procedure appears applicable for incorporation of a wide variety of amine-containing nonnatural amino acids into peptides. The particular modifications were intended to enhance physiochemical properties of NT(8-13) responsible for human NT 1 receptor (hNTR) binding, overall lipophilicity, and stability that may influence the potency of the peptides in vivo. When the peptides were tested for hNTR binding, the affinities in each series followed the order primary > secondary > tertiary > quaternary amine with the homolysine side-chain length being favored. All analogues possess binding affinities between acetyl-NT(8-13) and NT(8-13) indicating that the sterically less bulky alpha-azido may be inherently preferable to the acetyl group for N-terminal protection. This study extends the strategy of modifying amine-containing drugs through alkylations to peptide modification. The set of alkylated side chains also offers a new method of steric selection between receptor subtypes and could be used to modify the properties and biological effects of any peptide that contains cationic residues.

Preparation and receptor binding affinities of cyclic C-terminal neurotensin (8–13) and (9–13) analogues

Cyclic analogues of neurotensin (NT) C-terminal fragments NT(8–13) and NT(9–13) were produced via intramolecular nucleophilic substitution of the Tyr(11) phenoxide anion on a 6-bromohexanoyl side chain substituted at position 8 or 9 and tested for NT receptor binding affinity.

Correlative Ultrastructural Distribution of Neurotensin Receptor Proteins and Binding Sites in the Rat Substantia Nigra

Neurotensin (NT) produces various stimulatory effects on dopaminergic neurons of the rat substantia nigra. To gain insight into the subcellular substrate for these effects, we compared by electron microscopy the distribution of immunoreactive high-affinity NT receptor proteins (NTRH) with that of high-affinity 125I-NT binding sites in this region of rat brain. Quantitative analysis showed a predominant association of immunogold and radioautographic labels with somata and dendrites of presumptive dopaminergic neurons, and a more modest localization in myelinated and unmyelinated axons and astrocytic leaflets. The distributions of immunoreactive NTRH and 125I-NT binding sites along somatodendritic plasma membranes were highly correlated and homogeneous, suggesting that membrane-targeted NTRH proteins were functional and predominantly extrasynaptic. Abundant immunocytochemically and radioautographically labeled receptors were also detected inside perikarya and dendrites. Within perikarya, these were found in comparable proportions over membranes of smooth endoplasmic reticulum and Golgi apparatus, suggesting that newly synthesized receptor proteins already possess the molecular and conformational properties required for effective ligand binding. By contrast, dendrites showed a proportionally higher concentration of immunolabeled than radiolabeled intracellular receptors. A fraction of these immunoreactive receptors were found in endosomes, suggesting that they had undergone ligand-induced internalization and were under a molecular conformation and/or in a physical location that precluded their recognition by and/or access to exogenous ligand. Our results provide the first evidence that electron microscopic immunocytochemistry of the NT receptor identifies sites for both the binding and trafficking of NT in the substantia nigra.

Novel small molecule neurotensin antagonists: 3-(1,5-diaryl-1,5-dioxopentan-3-yl)benzoic acids

Screening in a neurotensin (NT) receptor binding assay resulted in the discovery of compound 1 with NT receptor binding affinity of 450 nM. SAR studies that varied substituents on each aromatic ring and the linking 1,5-pentanedione chain lead to compound 39 with 42 nM affinity. The more potent compounds were shown to be NT antagonists by their ability to inhibit NT induced calcium mobilization in HT29 cells.

Changes in gut neurotensin and modified colonic motility following whole-body irradiation in rat

Exposure to ionizing radiation induces gastrointestinal dysfunction often associated with disorders of intestinal motility. Neurotensin is one of the mediators involved in the control of intestinal muscle activity. The aim of this study was to relate neurotensin tissue content and specific receptor binding with contractile effect of neurotensin in rat colon after irradiation. Rats were exposed to whole-body gamma -irradiation (60Co;6 Gy). Intestinal (caecum, colon) neurotensin-like immunoreactivity, colonic muscle neurotensin receptor binding and neurotensininduced contractions in isolated colon were investigated 3 and 7 days after irradiation. Irradiation produced a marked increase in the intestinal muscle content of neurotensin-like immunoreactivity (2.5-fold in caecum, 5-fold in colon) 3 days post-irradiation. At 7 days, the intestinal neurotensin content was close to that of the control values. Three days after irradiation, neurotensin receptors in colonic muscle were characterized by the appearance of a transient second class of sites of low a ffinity-high capacity. A three-fold increase in the total number of sites was observed. In addition, effects of neurotensin on isolated colon preparations showed an increase (37%) of potency but a decrease (7-fold) of efficacy. Seven days after irradiation, the efficacy was close to the control. Modifications of intestinal neurotensin content and specific receptor characteristics induced by irradiation can influence the colonic contractile activity.

Characterization of the effect of SR48692 on inositol monophosphate, cyclic GMP and cyclic AMP responses linked to neurotensin receptor activation in neuronal and non-neuronal cells.

1. Neurotensin stimulated inositol monophosphate (IP1) formation in both human colonic carcinoma HT29 cells and in mouse neuroblastoma N1E115 cells with EC50 values of 3.5 +/- 0.5 nM (n = 4) and 0.46 +/- 0.02 nM (n = 3), respectively. Neurotensin also stimulated cyclic GMP production with an EC50 of 0.47 +/- 1.2 nM and inhibited cyclic AMP accumulation induced by forskolin (0.5 microM) with an IC50 of 1.33 +/- 1.5 nM (n = 3) on the N1E115 cell line. 2. The competitive antagonism by the non-peptide neurotensin receptor antagonist, SR48692 of neurotensin-induced IP1 formation revealed pA2 values of 8.7 +/- 0.2 (n = 3) for HT29 and 10.1 +/- 0.2 (n = 3) for N1E115 cells. SR48692 also antagonized the cyclic GMP and cyclic AMP responses induced by neurotensin in the N1E115 cell line with pA2 values of 10.7 +/- 0.7 (n = 3) and 9.8 +/- 0.3 (n = 3), respectively. 3. In CHO cells transfected with the rat neurotensin receptor, neurotensin stimulated IP1 and cyclic AMP formation with EC50 values of 3.0 +/- 0.5 nM (n = 3) and 72.2 +/- 20.7 nM (n = 3), respectively. Both effects were antagonized by SR48692, giving pA2 values of 8.4 +/- 0.1 (n = 3) for IP1 and 7.2 +/- 0.4 (n = 3) for cyclic AMP responses. 4. Radioligand binding experiments, performed with [125I]-neurotensin (0.2 nM), yielded IC50 values of 15.3 nM (n = 2) and 20.4 nM (n = 2) for SR48692 versus neurotensin receptor binding sites labelled in HT29 and N1E115 cells, respectively. 5 In conclusion, SR48692 appears to be a potent, species-independent antagonist of the signal transduction events triggered by neurotensin receptor activation in both neuronal and non-neuronal cell systems.

Agonist properties of a stable hexapeptide analog of neurotensin, NαMeArg-Lys-Pro-Trp-tLeu-Leu (NT1)

The major signal transduction pathway for neurotensin (NT) receptors is the G-protein-dependent stimulation of phospholipase C, leading to the mobilization of intracellular free Ca 2+ ([Ca 2+] i) and the stimulation of cyclic GMP. We investigated the functional actions of an analog of NT(8–13), N α MeArg-Lys-Pro-Trp-tLeu-Leu (NT1), and other NT related analogs by quantitative measurement of the cytosolic free Ca 2+ concentration in HT-29 (human colonic adenocarcinoma) cells using the Ca 2+-sensitive dye fura-2/AM and by effects on cyclic GMP levels in rat cerebellar slices. The NT receptor binding affinities for these analogs to HT-29 cell membranes and newborn (10-day-old) mouse brain membranes were also investigated. Data obtained from HT-29 cell and mouse brain membrane preparations showed saturable single high-affinity sites and binding densities ( B max) of 130.2 and 87.5 fmol/mg protein, respectively. The respective K D values were 0.47 and 0.39 nM, and the Hill coefficients were 0.99 and 0.92. The low-affinity levocabastine-sensitive site was not present ( K I > 10,000) in either membrane preparation. Although the correlation of binding betwen HT-29 cell membranes and mouse brain membranes was quite significant ( r = 0.92), some of the reference agents had lower binding affinities in the HT-29 cell membranes. The metabolically stable compound NT1 plus other NT analogs and related peptides [NT, NT(8–13), xenopsin, neuromedin N, NT(9–13), kinetensin and ( d-Trp 11)-NT] increased intracellular Ca 2+ levels in HT-29 cells, indicating NT receptor agonist properties. The effect of NT1 in mobilizing [Ca 2+] i blocked by SR 48692, a non-peptide NT antagonist. Receptor binding affinities of NT analogs to HT-29 cell membranes were positively correlated with potencies for mobilizing intracellular calcium in the same cells. In addition, NT1 increased cyclic GMP levels in rat cerebellar slices, confirming the latter findings of its NT agonist action. These results substantiate the in vitro NT agonist properties of the hexapeptide NT analog NT1.

Heterogeneity of melanized neurons expressing neurotensin receptor messenger RNA in the substantia nigra and the nucleus paranigralis of control and Parkinson's disease brain

We have recently cloned the neurotensin receptor from human substantia nigra. Using in situ hybridization techniques, with an 35S-labeled antisense RNA probe complementary to this receptor complementary DNA, we studied the expression of the human neurotensin receptor in the brain from control and Parkinson's disease subjects. We also performed an analogous study with rat brain. Neurotensin receptor messenger RNA was present in high levels in melanized neurons of the substantia nigra pars compacta and the nucleus paranigralis (the ventral tegmental area for rat brain). Background levels of signals for neurotensin receptor messenger RNA were detected in the nucleus ruber, the colliculus inferior and the striatal subdivisions (the nucleus caudatus, the putamen and the nucleus accumbens) of both human and rat brain. All these areas, except the nucleus ruber and the collicus inferior, contain very high to high levels of neurotensin receptor binding sites. Additionally, Parkinson's disease brains had markedly fewer melanized (possibly dopaminergic) neurons, as expected, and correspondingly very low or background levels of messenger RNA for neurotensin receptor. We have also demonstrated heterogeneity among the melanized cells expressing messenger RNA encoding the neurotensin receptor in the substantia nigra and the nucleus paranigralis of human brain. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. In general, the expression of the messenger RNA within the highly and evenly melanized neurons was lower than that found in low or unevenly pigmented neurons. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. The low pigmented neurons in the ventral tier of the substantia nigra had relatively high expression. On the other hand, highly and evenly melanized neurons in these regions of the brain had low expression of neurotensin receptor messenger RNA. Together with the previous binding data, it is suggested that not only in rat brain, but also in human brain, melanized (possibly dopaminergic) neurons in the substantia nigra and the nucleus paranigralis (ventral tegmental area of rat brain) synthesize neurotensin receptors and express them in their perikarya and the terminal regions. Additionally, the heterogeneity of the melanized neurons in human brain may play a role in the normal function of dopaminergic systems and probably in the etiology of some neurological and psychiatric disorders.

Neurotensin receptor binding and antinociceptive activity for lipophilic N α-amido neurotensin(9–13) analogs

A series of lipophilic N α-amido-neurotensin(9–13) analogs was prepared. These acylated pentapeptides exhibited good neurotensin receptor binding, as well as in vivo analgesic activity via i.c.v. and even intravenous routes of administration.

Identification of simpler analogs of neurotensin(9–13) which retain antinociceptive activity

The neurotensin C-terminal pentapeptide has been systematically simplified to identify a minimal fragment with in vivo analgesic activity and neurotensin receptor binding ability. Di-, tri-, and tetrapeptide fragments were inactive. Pentapeptide simplifications established that only the arginine could be replaced with simpler amino acids and retain activity in each assay. The neurotensin C-terminal pentapeptide, Arg-Pro-Tyr-Ile-Leu, is systematically simplified to identify a minimal fragment required for activity in both neurotensin receptor binding and in in vivo analgesic assay.

Patent Evaluation : WO9300359-: DuPont Merck Pharm Co: Novel neurotensin receptor antagonists

AbstractNovelty: Novel modified peptides bearing a lipophilic group that enables the compounds to penetrate the blood-brain barrier are claimed. The compounds are neurotensin analogues. Unlike neurotensin itself they exhibit analgesic and antipsychotic activities when administered in vivo and have a much improved duration of action.Biology: Compounds were screened for neurotensin receptor binding using the method of Goldert et al (Brain Research (1984) 324: 71–81). The specified compound had a Ki value of 117 nM. Analgesic activity was assessed using the PBQ-induced writhing test in mice. The specified peptide derivative was effective at a dose of 0.15μg/animal icv and had IC50 2.2 mg/kg iv.Chemistry: Forty-two compounds are exemplified by synthesis using standard techniques of peptide chemistry. Nα-(1-Adamantanecarbonyl)-Lys-Pro-Tyr-Ile-Leu is one of twenty-seven specifically claimed compounds.

Changes in neurotensin receptor binding in mice after chronic ethanol consumption.

Annals of the New York Academy of SciencesVolume 668, Issue 1 p. 314-316 Changes in Neurotensin Receptor Binding in Mice after Chronic Ethanol Consumptiona A. D. CAMPBELL, Corresponding Author A. D. CAMPBELL School of Pharmacy and Alcohol Research Center, University of Colorado, Boulder, Colorado 80309Address for correspondence: Andrew D. Campbell, School of Pharmacy, University of Colorado, Campus Box 297, Boulder, CO 80309-0297.Search for more papers by this authorV. G. ERWIN, V. G. ERWIN School of Pharmacy and Alcohol Research Center, University of Colorado, Boulder, Colorado 80309Search for more papers by this author A. D. CAMPBELL, Corresponding Author A. D. CAMPBELL School of Pharmacy and Alcohol Research Center, University of Colorado, Boulder, Colorado 80309Address for correspondence: Andrew D. Campbell, School of Pharmacy, University of Colorado, Campus Box 297, Boulder, CO 80309-0297.Search for more papers by this authorV. G. ERWIN, V. G. ERWIN School of Pharmacy and Alcohol Research Center, University of Colorado, Boulder, Colorado 80309Search for more papers by this author First published: October 1992 https://doi.org/10.1111/j.1749-6632.1992.tb27361.x a This work was supported by NIAAA Grants 00079, 03527, and 07330. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume668, Issue1The Neurobiology of NeurotensinOctober 1992Pages 314-316 RelatedInformation