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

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 chemotherapy-induced emesis.

• Authors: Yumi Watanabe, Hidetoshi Asai, Taketoshi Ishii, Satoko Kiuchi, Masahito Okamoto, Hiroyuki Taniguchi, Masaaki Nagasaki, Akira Saito
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 106 Issue 1 Pg. 121-7 (Jan 2008) ISSN: 1347-8613 [Print] Japan
• PMID: 18187929 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antiemetics
• Antineoplastic Agents
• Morpholines
• Neurokinin-1 Receptor Antagonists
• Peptide Fragments
• Piperidines
• Receptors, Neurokinin-1
• T-2328
• substance P, Sar(9)-Met(O2)(11)-
• GR 73632
• Aprepitant
• Substance P
• Cisplatin

Topics

• Animals
• Antiemetics (metabolism, pharmacology, therapeutic use)
• Antineoplastic Agents
• Aprepitant
• Binding Sites
• Brain (drug effects)
• CHO Cells
• Cell Line, Tumor
• Cisplatin
• Cricetinae
• Cricetulus
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Ferrets
• Gerbillinae
• Humans
• Kinetics
• Male
• Morpholines (metabolism, pharmacology, therapeutic use)
• Motor Activity (drug effects)
• Neurokinin-1 Receptor Antagonists
• Peptide Fragments (pharmacology)
• Piperidines (metabolism, pharmacology, therapeutic use)
• Receptors, Neurokinin-1 (metabolism)
• Substance P (analogs & derivatives, metabolism, pharmacology)
• Transfection
• Vomiting (chemically induced, prevention & control)