Potency, Efficacy, and Selectivity of GR64349 at Human Recombinant Neurokinin NK2 and NK1 Receptors

Publication date: Available online 22 August 2019Source: Neuroscience LettersAuthor(s): Elisabetta Perdona, Palmina Cavallini, Anna Sava, Cristiana Griffante, Daniel J. Ricca, Karl B. Thor, Nadia M.J. Rupniak, Mauro CorsiAbstractThe 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.
Source: Neuroscience Letters - Category: Neuroscience Source Type: research