Ritodrine inhibits neuronal nitric oxide synthase, a potential link between tocolysis and autism

• Published in: Medicinal chemistry research Vol. 23; no. 12; pp. 5102 - 5109
• Main Authors: Suaifan, Ghadeer A. R. Y., Shehadeh, Mayadah B., Al-Ijel, Hebah A. N., Al-Jamal, Khuloud T., Taha, Mutasem O.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2014
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Original Research; Pharmacology/Toxicology; Autism; Neuronal nitric oxide synthase; In vitro evaluation; Tocolysis; Molecular docking
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-014-1066-1

Statistical association between congenital autism and prenatal exposure to ritodrine (4-(2-((1 R ,2 S )-1-hydroxy-1-(4-hydroxyphenyl)propan-2-ylamino)ethyl)phenol) as a tocolytic agent was a matter of concern. Moreover, neuronal nitric oxide momentous role in various behavioral and cognitive functions was reported. In this context, a correlation between prenatal exposures to ritodrine, neuronal nitric oxide level and autism occurrence must be investigated. For this reason, we proposed possible inhibition of neuronal nitric oxide synthase (nNOS) by ritodrine. An insight toward our hypothesis approval was done through docking ritodrine into the catalytic pocket of nNOS. Apparently, ritodrine shared at least five critical binding interactions with a potent nNOS inhibitor (PDB code: JI7) . Subsequent in vitro experiment pointed out that ritodrine indeed inhibited the enzymatic activity of nNOS at low micromolar level. As a conclusion, ritodrine should not be used as a tocolytic agent but as a novel non peptidomimetic nNOS inhibitor lead scaffold for future optimization. Graphical Abstract (A) Ritodrine chemical structure (B) Docked pose of ritodrine into nNOS-binding pocket (PDB code: 3B3P, resolution 2.6 Ǻ) (C) Docked pose of inhibitor JI7 (green) as produced by docking simulation and the crystallographic structure of this inhibitor within nNOS