GR 46611 is a 5-HT1B and 5-HT1D receptor agonist, which can regulate the feeding behavior of animals[1]. GR 46611 enhances transporter ZnT8-dependent zinc import into insulin granules through stimulation of V-ATPase-driven acidification in β-cells and increases β-cell zinc content and augments β-cell-targeted drug delivery [2]. GR 46611 has been widely used in rat formalin tests to alleviate inflammatory pain [3].
In vitro, GR 46611 treatment (1μM) for 48 hours significantly promoted the proliferation of CCRF-CEM cells[4].
In vivo, GR 46611 treatment via daily intraperitoneal injection at a dose of 1mg/kg for 14 days significantly increased the seizure threshold of Dravet syndrome (DS) mice induced by hyperthermia, and reduced the severity of seizures and increased the survival rate of the mice[5]. A single injection of GR 46611 (30mg/kg) was administered, lasting for 3 hours, which significantly caused a decrease in rectal temperature in adult guinea pigs[6]. A single injection of GR 46611 (0.6nM; 1µl) via anterior portion of paraventricular thalamic nucleus reduced the pain threshold of mice within 24 hours and prolonged the immobility time in the forced swimming test (FST) and tail suspension test (TST)[7].
References:
[1] Da Silva R A, de Oliveira S T, Hackl L P N, et al. Ingestive behaviors and metabolic fuels after central injections of 5-HT1A and 5-HT1D/1B receptors agonists in the pigeon[J]. Brain research, 2004, 1026(2): 275-283.
[2] Lee S, Fraser H P, Schugar R C, et al. Pharmacologic stimulation of insulin granule acidification increases β-cell zinc content and augments β-cell-targeted drug delivery[J]. Journal of Biological Chemistry, 2025, 301(10).
[3] Granados-Soto V, Argüelles C F, Rocha-González H I, et al. The role of peripheral 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F serotonergic receptors in the reduction of nociception in rats[J]. Neuroscience, 2010, 165(2): 561-568.
[4] Sibella-Argüelles C. The proliferation of human T lymphoblastic cells induced by 5-HT1B receptors activation is regulated by 5-HT-moduline[J]. Comptes Rendus de l'Académie des Sciences-Series III-Sciences de la Vie, 2001, 324(4): 365-372.
[5] Hatini P G, Commons K G. A 5‐HT1D‐receptor agonist protects Dravet syndrome mice from seizure and early death[J]. European Journal of Neuroscience, 2020, 52(10): 4370-4374.
[6] Skingle M, Higgins G A, Feniuk W. Stimulation of central 5-HT1D receptors causes hypothermia in the guinea-pig[J]. Journal of Psychopharmacology, 1994, 8(1): 14-21.
[7] Cui M, Ji R, Song L, et al. Neuronal and molecular mechanisms underlying chronic pain and depression comorbidity in the paraventricular thalamus[J]. Journal of Neuroscience, 2024, 44(13).
GR 46611是一种5-HT1B和5-HT1D受体激动剂，可调节动物的摄食行为[1]。GR 46611通过刺激β细胞中V-ATP酶驱动的酸化作用，增强转运蛋白ZnT8依赖的锌向胰岛素颗粒的输入，增加β细胞锌含量，并增强β细胞靶向药物的递送[2]。GR 46611已被广泛用于大鼠福尔马林试验中以减轻炎性疼痛[3]。
在体外，1μM的GR 46611处理CCRF-CEM细胞48小时，显著促进了细胞增殖[4]。
在体内，每日腹腔注射1mg/kg剂量的GR 46611，持续14天，显著提高了Dravet syndrome (DS)小鼠由高热诱导的癫痫发作阈值，降低了癫痫发作的严重程度，并提高了小鼠的存活率[5]。单次注射30mg/kg剂量的GR 46611，持续3小时，显著降低了成年豚鼠的直肠温度[6]。通过丘脑室旁核前部单次注射GR 46611（0.6nM；1μl），在24小时内降低了小鼠的疼痛阈值，并延长了强迫游泳试验(FST)和悬尾试验(TST)中的不动时间[7]。