SR 48692 (Meclinertant) is an orally bioavailable, allosteric antagonist of the neuropeptide Y receptor NTS1 (Kd=3.4nM)[1, 2]. SR 48692 is the first non-peptide antagonist developed for NTS1, used in scientific research to explore the interactions of neuropeptide Y with other neurotransmitters in the brain[3]. SR 48692 enhances the sensitivity of ovarian cancer cells and experimental tumors to carboplatin[4]. SR 48692, when administered chronically via a central cannula to the paraventricular nucleus (PVN) of the hypothalamus, effectively attenuated the increase in central HPA axis activity caused by circadian rhythm fluctuations and stress responses[5].
In vitro, treatment of A375 melanoma cells with SR 48692 (5μM) for 1-4 days significantly inhibited neuropeptide-induced cell proliferation, inducing cell cycle arrest and apoptosis[6]. SR 48692 (5μM) also antagonized neuropeptide-induced increases in cytosolic Ca2+ in NCI-H209 cells[7].
In vivo, oral administration of SR 48692 (25mg/kg/day) for 5 days significantly inhibited tumor growth in mice bearing human prostate cancer cells (PC-3M-Luc cells) xenografts, and showed synergistic anti-tumor activity when combined with radiotherapy[8].
References:
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[2] Labbe-Jullie C, Botto J M, Mas M V, et al. [3H] SR 48692, the first nonpeptide neurotensin antagonist radioligand: characterization of binding properties and evidence for distinct agonist and antagonist binding domains on the rat neurotensin receptor[J]. Molecular pharmacology, 1995, 47(5): 1050-1056.
[3] Iyer M R, Kunos G. Therapeutic approaches targeting the neurotensin receptors[J]. Expert Opinion on Therapeutic Patents, 2021, 31(5): 361-386.
[4] Liu J, Agopiantz M, Poupon J, et al. Neurotensin receptor 1 antagonist SR48692 improves response to carboplatin by enhancing apoptosis and inhibiting drug efflux in ovarian cancer[J]. Clinical Cancer Research, 2017, 23(21): 6516-6528.
[5] Rowe W B, Nicot A, Sharma S, et al. Central administration of the neurotensin receptor antagonist, SR48692, modulates diurnal and stress-related hypothalamic-pituitary-adrenal activity[J]. Neuroendocrinology, 1997, 66(2): 75-85.
[6] Zhang Y, Zhu S, Yi L, et al. Neurotensin receptor1 antagonist SR48692 reduces proliferation by inducing apoptosis and cell cycle arrest in melanoma cells[J]. Molecular and cellular biochemistry, 2014, 389(1): 1-8.
[7] Moody T W, Chiles J, Casibang M, et al. SR48692 is a neurotensin receptor antagonist which inhibits the growth of small cell lung cancer cells[J]. Peptides, 2001, 22(1): 109-115.
[8] Valerie N C K, Casarez E V, DaSilva J O, et al. Inhibition of neurotensin receptor 1 selectively sensitizes prostate cancer to ionizing radiation[J]. Cancer research, 2011, 71(21): 6817-6826.