GR 46611

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).