Identification of N-[(5-{[(4-Methylphenyl)sulfonyl]amino}-3-(trifluoroacetyl)-1H-indol-1-yl)acetyl]-l-leucine (NTRC-824), a Neurotensin-like Nonpeptide Compound Selective for the Neurotensin Receptor Type 2

Abstract

Compounds acting via the neurotensin receptor type 2 (NTS2) are known to be active in animal models of acute and chronic pain. To identify novel NTS2 selective analgesics, we searched for NTS2 selective nonpeptide compounds using a FLIPR assay and identified the title compound (NTRC-824, 5) that, to our knowledge, is the first nonpeptide that is selective for NTS2 versus NTS1 and behaves like the endogenous ligand neurotensin in the functional assay.

The amide linker in nonpeptide neurotensin receptor ligands plays a key role in calcium signaling at the neurotensin receptor type 2

“…In this case, 16b showed competitive (surmountable) antagonist activity whereas both NT and 6 demonstrated insurmountable antagonism of the calcium release mediated by compound 2 . 21,22 In fact, 16b was the first competitive antagonist observed in our studies of nonpeptide NTS2 compounds. The napthyl substituted compound 7 showed substantially improved antagonist activity compared with 16b (K e of 181 versus 3046 nM respectively).…”

“… a [ 125 I]NT, b K e , EC 50 , and K i values are nM±SEM, c E max value is % of 2 , d Data, except for NTS1 binding, is from Ref 22, e Not determined, f Not active. …”

“…This feature differentiates compound 7 from the insurmountable antagonists described in previous work. 22 As such, compound 7 provides an additional tool to further our understating of the relevance of calcium signaling at NTS2 to analgesia in relevant animal models. These studies are currently in progress and will be reported in the near future.…”

Synthesis, Biological Evaluation and Molecular Docking Studies of the 7-Acetamido Substituted 2-Aryl-5-bromo-3-trifluoroacetylindoles as Potential Inhibitors of Tubulin Polymerization

“…1H-indol-1-yl)acetyl]-L-leucine (NTRC-824) shown in Figure 1, which was isolated as an impurity was 90-fold more active (IC50 = 38 nM) and selective for the neurotesin receptor type 2 (NTS2 versus NTS1) than the expected C-3 unsubstituted analogue (IC50 = 3322 nM) [10]. The enhanced activity of NTRC-824 is presumably due to the increased electron withdrawing effect of the trifluoromethyl group, which has been found to generally increase the lipophilicity, metabolic stability and activity profile compared to that of the 3-unsubstituted or 3-acetyl analogues [2,[11][12][13].…”

Identification of N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (NTRC-808), a novel nonpeptide chemotype selective for the neurotensin receptor type 2

“…30 More recently, we identified an NT-like antagonist 7 starting from the screening of a library of substituted indole compounds based upon the NTS1 partial agonist 8. 31,32 In this article, we report the discovery of N -{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-L-leucine (NTRC-808, 9 ) a novel nonpeptide chemotype that shows potent partial agonist activity in the FLIPR functional assay and is selective for NTS2 versus NTS1. The discovery of this compound was accomplished in a different manner from the two described above as we used a pharmacophore model and database mining strategy to obtain our initial hit compound rather than adjusting the activity of a scaffold previously shown to bind NT receptors.…”