SR 48692

Ki: 8.6 nM for HT-29 cells

SR 48692 is a nonpeptide neurotensin antagonist.

Neurotensin is a tridecapeptide and is distributed in both the central and peripheral nervous systems. Neurotensin shows a wide spectrum of biological activities resulting in fulfilling a dual function as a neurotransmitter/neuromodulator in the brain and working as a hormone/cellular mediator in peripheral tissues.

In vitro: SR 48692 was found to inhibit the binding of [3H]- or [125I]-neurotensin to membrane preparations from mouse brains and HT-29 cells. In HT-29 cells, SR 48692 also antagonized the neurotensin-induced mobilization of intracellular calcium, which was consistent with previous findings. Moreover, in rat cerebellar slices, SR 48692 could block the cyclic GMP level increase in a dose-dependent manner [1].

In vivo: SR 48692 could antagonize the increase in rat brain mesolimbic dopamine turnover which was induced by the systemically active neurotensin peptide EI. Whereas, SR 48692 did not antagonize EI-induced decrease in mouse body temperature and spontaneous locomotor activity [1].

Clinical trial: In a clinical study, SR 48692 was used to assess the effect of endogenous neurotensin on lower oesophageal sphincter function. Results showed that SR 48692, however, had no effect on oesophageal motility in humans [2].

References:
[1] Pugsley TA,Akunne HC,Whetzel SZ,Demattos S,Corbin AE,Wiley JN,Wustrow DJ,Wise LD,Heffner TG.  Differential effects of the nonpeptide neurotensin antagonist, SR 48692, on the pharmacological effects of neurotensin agonists. Peptides.1995;16(1):37-44.
[2] Zerbib F,Piche T,Charles F,Galmiche JP,Bruley des Varannes S. SR 48692, a specific neurotensin receptor antagonist, has no effect on oesophageal motility in humans. Aliment Pharmacol Ther.2004 Apr 15;19(8):931-9.

Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats.[Pubmed:17014260]

Behav Neurosci. 2006 Oct;120(5):1093-102.

The involvement of neurotensin (NT) within the nucleus accumbens core (NAC) in behavior has been sparsely investigated. Moreover, little is known of what role NT within the ventral striatum has on spatial learning. The present study investigated whether NT receptors in the NAC are implicated in learning of spatial information. Male Long-Evans rats were trained on a food search spatial learning task. Rats were microinfused with either NT antagonist SR 48692 (50 nM/0.5 =L) or saline in the NAC before each training session. Rats treated with SR 48692 made more reference and working memory errors during the acquisition of spatial learning than did rats infused with saline. These results suggest that NT receptors contribute to NAC-mediated spatial learning.

Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1.[Pubmed:21272935]

Neuropeptides. 2011 Apr;45(2):151-6.

The presence of neurotensin and neurotensin receptors has been demonstrated in human pancreatic carcinomas using autoradiography and Northern blot analysis. In vitro studies have reported that the neurotensin antagonist SR 48692 could inhibit the growth of MIA PaCa-2 cells in a neurotensin mediated fashion, and neurotensin could overcome this inhibition or stimulate proliferation. However, it is currently unknown whether such actions are exerted on PANC-1 cells. In addition, the immunolocation of neurotensin and neurotensin receptors is still unclear in human pancreatic ductal carcinoma tissues. Immunohistochemistry was applied to detect the distribution of neurotensin and neurotensin receptor subtype-1 in human pancreatic ductal carcinoma and normal pancreatic tissues. Furthermore, an in vitro study was carried out to test the pharmacological profile of neurotensin and SR 48692 in human pancreatic ductal carcinoma cell line PANC-1. Compared with normal pancreatic tissues, pancreatic ductal carcinoma tissues have higher neurotensin and neurotensin receptor subtype-1 expression rates. Pancreatic ductal carcinomas (32/40) bear the expression of both neurotensin and neurotensin receptor subtype-1. We observed that neurotensin (10(-)(1)(1)-10(-)(7) M) significantly stimulated the proliferation of PANC-1 and SR 48692 (10(-)(1)(1)-10(-)(7) M) alone had no effect on the growth of PANC-1 cells; however, SR 48692 (10(-)(1)(0)-10(-)(6) M) inhibited the stimulatory effect of neurotensin (10(-)(9) M). Considering the overexpression of both neurotensin and neurotensin receptor subtype-1 in pancreatic ductal carcinomas, it could enable us to develop markers for pancreatic cancer diagnosis. As SR 48692 could inhibit neurotensin induced cell growth, neurotensin receptor subtype-1 may serve as a therapeutic target for the therapy of pancreatic carcinomas. Furthermore, our study indicates that the counteraction of neurotensin and neurotensin receptor subtype-1 regulates the genesis and development of pancreatic carcinomas.

The synthesis of neurotensin antagonist SR 48692 for prostate cancer research.[Pubmed:23721919]

Bioorg Med Chem. 2013 Jul 15;21(14):4378-87.

An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.

SR 48692, a specific neurotensin receptor antagonist, has no effect on oesophageal motility in humans.[Pubmed:15080855]

Aliment Pharmacol Ther. 2004 Apr 15;19(8):931-9.

BACKGROUND: The administration of exogenous neurotensin can reduce the lower oesophageal sphincter pressure, but it is unclear whether this effect is pharmacological or physiological. AIM: A specific neurotensin receptor antagonist (SR 48692) was used to assess the effect of endogenous neurotensin on lower oesophageal sphincter function. METHODS: Twenty-four healthy male subjects were included in a double-blind, placebo-controlled, randomized, cross-over study designed to determine the effects of two single doses (90 and 300 mg, preceded by a loading dose) of SR 48692 on the resting lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations, primary oesophageal peristalsis and oesophageal acid exposure. Oesophageal pH and motility recordings were performed during 1 h of fasting and 3 h post-prandially. Plasma neurotensin-like immunoreactivity release was determined by radioimmunoassay. RESULTS: During fasting, the lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxation rate and reflux episodes were similar with the two doses of SR 48692 and placebo. Meal ingestion induced a rise in plasma neurotensin-like immunoreactivity, a decrease in lower oesophageal sphincter pressure and an increase in both the transient lower oesophageal sphincter relaxation rate and the number of reflux episodes, which were not significantly modified by SR 48692. SR 48692 did not affect oesophageal primary peristalsis. CONCLUSION: This study shows that SR 48692, a specific neurotensin 1 receptor antagonist, has no effect on oesophageal motility in humans.

The identification of nonpeptide neurotensin receptor partial agonists from the potent antagonist SR48692 using a calcium mobilization assay.[Pubmed:19195889]

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1438-41.

In a search for nonpeptide agonists for the neurotensin receptor (NTR1), we replaced the adamantyl amino acid moiety found in the antagonist SR48692 (1a) with leucine and related alpha-alkylamino acids found in peptide agonists. When tested in a calcium mobilization assay, we found that both d- and l-leucine confer partial agonist activity to the pyrazole scaffold with the l-enantiomer (3a) providing a significantly greater response. A brief SAR survey demonstrated that the observed agonist activity was resilient to changes made to the dimethoxyaryl ring in 3a. The resulting compounds were less potent relative to 3a but showed greater agonist responses. The partial agonist activity was extinguished when the chloroquinoline ring was replaced with naphthalene. Thus, while l-leucine appears to possess a powerful agonist directing affect for the NTR1 receptor, its presence alone in the molecular architecture is not sufficient to insure agonist behavior.

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.[Pubmed:8528577]

Br J Pharmacol. 1995 Sep;116(2):1899-905.

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.

Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor.[Pubmed:8380498]

Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):65-9.

We describe the characteristics of SR 48692, a selective, nonpeptide antagonist of the neurotensin receptor. In vitro, this compound competitively inhibits 125I-labeled neurotensin binding to the high-affinity binding site present in brain tissue from various species with IC50 values of 0.99 +/- 0.14 nM (guinea pig), 4.0 +/- 0.4 nM (rat mesencephalic cells), 7.6 +/- 0.6 nM (COS-7 cells transfected with the cloned high-affinity rat brain receptor), 13.7 +/- 0.3 nM (newborn mouse brain), 17.8 +/- 0.9 nM (newborn human brain), 8.7 +/- 0.7 nM (adult human brain), and 30.3 +/- 1.5 nM (HT-29 cells). It also displaces 125I-labeled neurotensin from the low-affinity levocabastine-sensitive binding sites but at higher concentrations (34.8 +/- 8.3 nM for adult mouse brain and 82.0 +/- 7.4 nM for adult rat brain). In guinea pig striatal slices, SR 48692 blocks K(+)-evoked release of [3H]dopamine stimulated by neurotensin with a potency (IC50 = 0.46 +/- 0.02 nM) that correlates with its binding affinity. In a cell line derived from a human colon carcinoma (HT-29), SR 48692 competitively antagonizes neurotensin-induced intracellular Ca2+ mobilization with a pA2 (-log Kapp) values of 8.13 +/- 0.03, which is consistent with results obtained in binding studies. Moreover, SR 48692 is devoid of any intrinsic agonist activity. This compound is also active in vivo, since it reverses at low dose (80 micrograms/kg) the turning behavior induced by intrastriatal injection of neurotensin in mice with similar potency whatever the route of administration (i.p. or orally) and with a long duration of action (6 hr). Thus, being a potent and selective neurotensin receptor antagonist, SR 48692 may be considered as a powerful tool for investigating the role of neurotensin in physiological and pathological processes.

Meclinertant (SR 48692) is a potent, selective, nonpeptide and orally active neurotensin receptor 1 (NTS1) antagonist. In human colon carcinoma (HT-29) cells, Meclinertant competitively antagonizes neurotensin-induced intracellular Ca2+ mobilization with a pA2 values of 8.13. Meclinertant has anxiolytic, anti-addictive and memory-impairing effects.

SR 48692,146362-70-1,Natural Products,Neurotensin Receptors, buy SR 48692 , SR 48692 supplier , purchase SR 48692 , SR 48692 cost , SR 48692 manufacturer , order SR 48692 , high purity SR 48692