QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.029868v1 71/3/902    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tian, G. Articles by Scott, C. W. Search for Related Content PubMed PubMed Citation Articles by Tian, G. Articles by Scott, C. W.

Neurokinin-3 Receptor-Specific Antagonists Talnetant and Osanetant Show Distinct Mode of Action in Cellular Ca²⁺ Mobilization but Display Similar Binding Kinetics and Identical Mechanism of Binding in Ligand Cross-Competition

Department of Lead Generation, AstraZeneca Pharmaceuticals, Wilmington, Delaware

Talnetant and osanetant, two structurally diverse antagonists of neurokinin-3 receptor (NK₃), displayed distinct modes of action in Ca²⁺ mobilization. Although talnetant showed a normal Schild plot with a slope close to unity and a K_b similar to its K_i value in binding, osanetant presented an aberrant Schild with a steep slope (3.3 ± 0.5) and a K_b value (12 nM) significantly elevated compared with its K_i value (0.8 nM) in binding. Kinetic binding experiments indicated a simple one-step binding mechanism with relatively fast on- and off-rates for both antagonists, arguing against slow onset of antagonism as the reason for abnormal Schild. This conclusion was supported by prolonged preincubation of antagonist that failed to improve the observed aberrant Schild. In ligand cross-competition binding, both talnetant and osanetant displayed linear reciprocal plots of identical slope when [MePhe⁷]neurokinin B (NKB) was used as the other competition partner with ¹²⁵I-[MePhe⁷]NKB as the radioligand, indicating competitive binding of either antagonist with regard to [MePhe⁷]NKB. Similar patterns were obtained when talnetant was tested against osanetant, indicating competitive binding between the two antagonists as well. These results were reproduced when [³H]4-quinolinecarboxamide (SB222200), a close derivative of talnetant, was used as the radioligand. Taken together, these data strongly suggest binding of both talnetant and osanetant at the orthosteric binding site with similar kinetic properties and do not support the hypothesis that the aberrant Schild observed in functional assays for osanetant is derived from differences in the mechanism of binding for these NK₃ antagonists.

Address correspondence to: Dr. Gaochao Tian, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19803. E-mail: gaochao.tian{at}astrazeneca.com

This article has been cited by other articles:

				P. Malherbe, C. Bissantz, A. Marcuz, C. Kratzeisen, M.-T. Zenner, J. G. Wettstein, H. Ratni, C. Riemer, and W. Spooren Me-Talnetant and Osanetant Interact within Overlapping but Not Identical Binding Pockets in the Human Tachykinin Neurokinin 3 Receptor Transmembrane Domains Mol. Pharmacol., June 1, 2008; 73(6): 1736 - 1750. [Abstract] [Full Text] [PDF]