Potency, efficacy, and selectivity of GR64349 at human recombinant neurokinin NK2 and NK1 receptors

• Published in: Neuroscience letters Vol. 711; p. 134456
• Main Authors: Perdona, Elisabetta, Cavallini, Palmina, Sava, Anna, Griffante, Cristiana, Ricca, Daniel J., Thor, Karl B., Rupniak, Nadia M.J., Corsi, Mauro
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15-10-2019
• Subjects: GR64349; NK1 receptor; Tachykinin NK2 receptor; NK1 receptor; Tachykinin NK2 receptor; GR64349
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2019.134456

•The affinity and potency of GR64349 for NK2 and NK1 receptors was examined.•Binding affinity was ˜1200-fold higher for NK2 than NK1 receptors.•Potency was 500-1,400-fold higher at NK2 than NK1 receptors in functional assays.•GR64349 is the most selective NK2 receptor agonist described to date.
The affinity, potency, efficacy, and selectivity of the NK2 receptor agonist GR64349 ([Lys3,Gly8,-R-γ-lactam-Leu9]NKA(3–10)) at human recombinant NK2 and NK1 receptors was examined. In radioligand binding studies, GR64349 displaced [125I]-NKA binding to NK2 receptors with high affinity (pKi 7.77 + 0.10) but only weakly displaced [3H]-septide binding to NK1 receptors (pKi <5). In functional studies examining increases in intracellular inositol-1 phosphate (IP-1) accumulation, calcium levels, and cyclic AMP synthesis, GR64349 was a full agonist by reference to the endogenous agonists NKA (NK2 receptors) and substance P (NK1 receptors). GR64349 increased IP-1 accumulation with 1,400-fold greater potency in cells expressing NK2 receptors (pEC50 9.10 + 0.16) than cells expressing NK1 receptors (pEC50 5.95 + 0.80). For calcium responses, GR64349 was 500-fold more potent in the assay using NK2 receptors (pEC50 9.27 + 0.26) than NK1 receptors (pEC50 6.55 + 0.16). GR64349 also stimulated cyclic AMP synthesis in both cell lines, and was almost 900-fold more potent at NK2 receptors (pEC50 10.66 + 0.27) than NK1 receptors (pEC50 7.71 + 0.41). These findings confirm that GR64349 is the most selective NK2 receptor agonist described to date.