Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors

Autor: Anna Sava, Palmina Cavallini, Daniel J. Ricca, Nadia M.J. Rupniak, Mauro Corsi, Elisabetta Perdona, Edward C. Burgard, Karl B. Thor, Cristiana Griffante
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Neurokinin A
Drug Evaluation
Preclinical
Receptor agonist activity
lcsh:Medicine
Stimulation
Peptide
Biochemistry
Intracellular Receptors
chemistry.chemical_compound
Binding Analysis
0302 clinical medicine
Cell Signaling
Cricetinae
Cyclic AMP
Membrane Receptor Signaling
Receptor
lcsh:Science
chemistry.chemical_classification
Multidisciplinary
integumentary system
Chemistry
Chinese hamster ovary cell
hemic and immune systems
Receptors
Neurokinin-2
Receptors
Neurokinin-1
respiratory system
Recombinant Proteins
Enzymes
Optical Equipment
030220 oncology & carcinogenesis
Cell lines
Engineering and Technology
Biological cultures
Oxidoreductases
Luciferase
Research Article
Signal Transduction
Cell Binding
Cell Physiology
Equipment
CHO Cells
Research and Analysis Methods
03 medical and health sciences
Cricetulus
Potency
Animals
Humans
Receptor Binding Assays
Chemical Characterization
EC50
Dose-Response Relationship
Drug
Cell Membrane
lcsh:R
Biology and Life Sciences
Proteins
Reproducibility of Results
Prisms
Cell Biology
Molecular biology
Enzymology
Calcium
lcsh:Q
Peptides
030217 neurology & neurosurgery
Zdroj: PLoS ONE, Vol 13, Iss 10, p e0205894 (2018)
PLoS ONE
ISSN: 1932-6203
Popis: A series of peptide NK2 receptor agonists was evaluated for affinity, potency, efficacy, and selectivity at human recombinant NK2 and NK1 receptors expressed in CHO cells to identify compounds with the greatest separation between NK2 and NK1 receptor agonist activity. Binding studies were performed using displacement of [125I]-NKA binding to NK2 receptors and displacement of [3H]-Septide binding to NK1 receptors expressed in CHO cells. Functional studies examining the increase in intracellular calcium levels and cyclic AMP stimulation were performed using the same cell lines. A correlation was demonstrated between binding affinities (Ki) and potency to increase intracellular calcium (EC50) for NK2 and NK1 receptors. Ranking compounds by their relative affinity (Ki) or potency (EC50) at NK2 or NK1 receptors indicated that the most selective NK2 agonists tested were [Lys5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 674; NK1/NK2 EC50 ratio = 105) and [Arg5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 561; NK1/NK2 EC50 ratio = 70). The endogenous peptide, NKA, lacked selectivity with an NK1/NK2 Ki ratio = 20 and NK1/NK2 EC50 ratio = 1. Of the compounds selected for evaluation in cyclic AMP stimulation assays, [β-Ala8]-NKA(4-10) had the greatest selectivity for activation of NK2 over NK1 receptors (NK1/NK2 EC50 ratio = 244), followed by [Lys5,MeLeu9,Nle10]-NKA(4-10) (ratio = 74), and NKA exhibited marginal selectivity (ratio = 2.8).
Databáze: OpenAIRE
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