Pharmacological Characterization of T-2328, 2-Fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile Dihydrochloride, as a Brain-Penetrating Antagonist of Tachykinin NK1 Receptor

Abstract

Abstract. The pharmacological properties of T-2328 were evaluated as an antagonist of the tachykinin neurokinin 1 (NK 1 ) receptor. T-2328 inhibited the specific binding of [ 3 H][Sar 9 ,Met(O 2 ) 11 ]substance P to tachykinin NK 1 receptors in human lymphoblastic IM9 cells with K i of 0.08 nM. In the same assay, K i for aprepitant, a brain-penetrating NK 1 antagonist, was 1.3 nM. The antagonism of T-2328 is highly selective for the human NK 1 receptors since the affinities for human NK 2 , NK 3 receptors, and 13 other kinds of receptors and ion channels were >1000-fold lower than for NK 1 receptors. Reduction in Bmax with no change in affinity suggests the non-competitive nature of T-2328 interaction with the NK 1 receptor. T-2328 (0.03 -0.1 mg / kg, i.v.) and aprepitant (1 -3 mg / kg, i.v.) significantly prevented the GR73632 (i.c.v.)-induced foot tapping response in gerbils. The potencies of T-2328 in both in vitro and in vivo studies were more than 10 times greater than those of aprepitant. I.v. administration of T-2328 (0.1 -0.3 mg/ kg) potently blocked both acute and delayed emetic responses induced by cisplatin (5 mg / kg, i.p.) in ferrets. It is concluded that T-2328 is a potent, centrally active NK 1 antagonist. T-2328 may have potential as a novel therapeutic agent for the treatment of chemotherapyinduced emesis.

Treatment with the NK1 Antagonist Emend Reduces Blood Brain Barrier Dysfunction and Edema Formation in an Experimental Model of Brain Tumors

“…Emend was prepared by dissolving the drug in saline, with the vehicle control animals administered saline only. The dose of Emend was determined from previous studies, which have demonstrated this administration exerts central effects [17]. The dexamethasone dosage has been successfully used previously to treat experimental brain tumor associated edema [18].…”

Polyfluorinated Groups in Medicinal Chemistry

“…Aprepitant 8 (Emend, Figure 2C) was the first drug available on the market for the treatment of vomiting and nausea caused by chemotherapy regimen [29]. It exerts its action by blocking the neuro- Polyfluorinated groups in medicinal chemistry Review kinin-1 (NK-1) receptor.…”

Olanzapine-Based Triple Regimens Versus Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting Associated with Highly Emetogenic Chemotherapy: A Network Meta-Analysis

“…CINV can be classified as acute phase (0–24 hours after chemotherapy) or delayed phase (24–120 hours after chemotherapy) based on the time of incidence. Neurokinin‐1 receptor antagonists (NK‐1RAs), a novel class of antiemetic medications including aprepitant, casopitant, fosaprepitant, netupitant, rolapitant, and others, play an efficient role in both acute and delayed CINV control by blocking the binding of substance P to the NK‐1R in the vomiting center of the central nervous system . Recently, a large‐scale network meta‐analysis has further confirmed that different NK‐1RAs‐based triple regimens (NK‐1RAs + serotonin receptor antagonist [5‐HT 3 RA] + corticosteroids) shared equivalent effect on CINV control in all the phases.…”