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:
[1] Gully D, Canton M, Boigegrain R, et al. Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor[J]. Proceedings of the National Academy of Sciences, 1993, 90(1): 65-69.
[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.
SR 48692（Meclinertant）是一种口服可生物利用的神经降压素受体NTS1的变构拮抗剂（Kd=3.4nM）[1, 2]。SR 48692是首个为NTS1开发的非肽拮抗剂，用于科学研究中探索神经肽Y与大脑中其他神经递质的相互作用[3]。SR 48692增强了卵巢癌细胞和实验性肿瘤对卡铂的敏感性[4]。SR 48692通过植入中央导管慢性输注至下丘脑室旁核（PVN），有效减弱了昼夜节律波动和应激反应所引起的中枢HPA活动升高[5]。
在体外，SR 48692（5μM）处理A375黑色素瘤细胞1-4天，显著抑制了神经肽素（NTS）引起的细胞增殖，诱导了细胞周期阻滞和细胞凋亡[6]。SR 48692（5μM）处理NCI-H209 细胞，拮抗了神经肽（NT）引起的胞质Ca2+升高的能力[7]。
在体内，SR 48692（25mg/kg/day）通过口服治疗人前列腺癌细胞（PC-3M-Luc细胞）异种移植小鼠5天，显著抑制了小鼠体内肿瘤生长，与放射治疗联合使用产生协同抗肿瘤活性[8]。