L-733,060 hydrochloride

Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer.[Pubmed:24030979]

Cancer Res. 2013 Nov 1;73(21):6424-34.

ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored.

The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists.[Pubmed:12225694]

Neuropsychopharmacology. 2002 Sep;27(3):371-9.

Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on an adapted elevated plus-maze, and the ability of anxiolytic drugs to produce anti-anxiety effects in the gerbil elevated plus-maze. The aim of the present study was to determine whether oral (p.o.) administration of the NK1 receptor antagonists MK-869, L-742,694, L-733,060, CP-99,994, and CP-122,721 produced anxiolytic-like effects in the gerbil elevated plus-maze. Upon testing, all five NK1 antagonists produced anxiolytic-like effects. MK-869 (0.01-3 mg/kg) was the most potent NK1 antagonist, producing anxiolytic-like effects on percentage of open arm time, percentage of open arm entries, stretch-attend postures, and head dips at 0.03-0.3 mg/kg doses. L-742,694 (1-30 mg/kg) and L-733,060 (1-10 mg/kg) produced anxiolytic-like effects on percentage of open arm time and stretch-attend postures at 3-10 mg/kg doses. CP-99,994 (3-30 mg/kg) only produced an anxiolytic-like effect on stretch-attend postures. CP-122,721 (3-30 mg/kg) produced an anxiolytic-like effect on percentage of open arm time at 30 mg/kg. The order of potency of the NK1 antagonists to increase percentage of open arm time was very similar to their potency to block NK1 agonist-induced foot-tapping. These studies demonstrate that neurokinin NK1 receptor antagonists produce anxiolytic-like effects in a novel gerbil elevated plus-maze, and suggest that this is an appropriate model to test NK1 antagonists for preclinical anxiolytic activity.

Distinct mechanism for antidepressant activity by blockade of central substance P receptors.[Pubmed:9733503]

Science. 1998 Sep 11;281(5383):1640-5.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays.[Pubmed:8982729]

Eur J Pharmacol. 1996 Dec 12;317(1):129-35.

This study investigated the properties of a novel piperidine ether-based tachykinin NK1 receptor antagonist L-733,060, ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine and its 2R,3R-enantiomer L-733,061 on [Ca2+]i mobilisation in Chinese hamster ovary cells transfected with human tachykinin NK1 receptors, compared to their effects in rodent cardiovascular and neurogenic plasma extravasation assays. Using FURA-2-imaging techniques, L-733,060 inhibited substance P-induced [Ca2+]i mobilisation with an estimated affinity of 0.8 nM whereas L-733,061 (30-300 nM) did not. No significant effects of L-733,060 were observed on mean arterial blood pressure or heart rate in conscious or anaesthetised rats at doses of < 3000 micrograms kg-1 i.v. L-733,060 also stereoselectively inhibited neurogenic plasma extravasation in rat dura produced by electrical stimulation of trigeminal nerves with an ID50 of 212 +/- 19 micrograms kg-1 i.v. Thus, L-733,060 is a novel antagonist of human tachykinin NK1 receptors which stereoselectively inhibits neurogenic plasma extravasation at doses that do not cause adverse cardiovascular effects.