Vofopitant

Vofopitant is a neurokinin-1 (NK₁) receptor antagonist (K_i = 0.03 nM for the human receptor).¹ It is selective for NK₁ over NK₂ and NK₃ receptors (IC₅₀s = >10,000 nM for both), the serotonin (5-HT) receptor subtypes 5-HT_1A, 5-HT_1D, and 5-HT_2A (K_is = 501, 251, and 316 nM, respectively), and histamine H₁ and H₂ receptors (K_is = 316 and 251 nM, respectively). It inhibits systemic vascular leakage induced by resiniferatoxin in guinea pigs (ID₅₀ = 0.007 mg/kg).² Vofopitant (0.1 mg/kg) inhibits retching and vomiting induced by various emetogens in ferrets.¹ It increases the number of entries into the open arms of the elevated plus maze in gerbils when administered at doses ranging from 0.3 to 5 mg/kg and increases the percentage of time spent in the open arms at 5 mg/kg, indicating anxiolytic-like activity.³ Vofopitant potentiates the reduction in immobility time induced by citalopram (Item No. 14572) in the forced swim test in mice when administered at a dose of 40 mg/kg but inhibits the reduction in social interaction induced by citalopram in rats and gerbils at 0.63 and 10 mg/kg, indicating potentiation and inhibition of citalopram-induced antidepressant-like and anxiety-like behaviors, respectively.⁴

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1. Gardner, C.J., Armour, D.R., Beattie, D.T., et al. GR205171: A novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity. Regul. Pept. 65(1), 45-53 (1996).

2. Hale, J.J., Mills, S.G., MacCoss, M., et al. Structural optimization affording 2-(<em>R</em>)-(1-(<em>R</em>)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(<em>S</em>)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J. Med. Chem. 41(23), 4607-4614 (1998).

3. Heldt, S.A., Davis, M., Ratti, E., et al. Anxiolytic-like effects of the neurokinin 1 receptor antagonist GR-205171 in the elevated plus maze and contextual fear-potentiated startle model of anxiety in gerbils. Behav. Pharmacol. 20(7), 584-595 (2009).

4. Gobert, A., Brocco, M., Dekeyne, A., et al. Neurokinin1 antagonists potentiate antidepressant properties of serotonin reuptake inhibitors, yet blunt their anxiogenic actions: A neurochemical, electrophysiological, and behavioral characterization. Neuropsychopharmacology 34(4), 1039-1056 (2009).