ORIGINAL RESEARCH Ritodrine inhibits neuronal nitric oxide synthase, a potential link between tocolysis and autism Ghadeer A. R. Y. Suaifan • Mayadah B. Shehadeh • Hebah A. N. Al-Ijel • Khuloud T. Al-Jamal • Mutasem O. Taha Received: 17 January 2014 / Accepted: 2 June 2014 / Published online: 27 June 2014 Ó Springer Science+Business Media New York 2014 Abstract Statistical association between congenital aut- ism and prenatal exposure to ritodrine (4-(2-((1R,2S)-1- hydroxy-1-(4-hydroxyphenyl)propan-2-ylamino)ethyl)phe- nol) as a tocolytic agent was a matter of concern. More- over, neuronal nitric oxide momentous role in various behavioral and cognitive functions was reported. In this context, a correlation between prenatal exposures to rito- drine, 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. Keywords Autism  Molecular docking  In vitro evaluation  Neuronal nitric oxide synthase  Tocolysis Introduction Preterm birth is the leading cause of prenatal mortality and morbidity (Dennedy et al., 2001; Schwarz and Page, 2003). It is one of the most important clinical problems in the developed countries and throughout the world (Berkman et al., 2003; Derbent et al., 2011). Tocolytic drugs such as beta-adrenergic agonists (e.g., ritodrine, fenoterol, salbutamol, terbutaline), calcium channel blockers (e.g., nifedipine), magnesium (magne- sium oxide, magnesium chloride, magnesium gluconate and magnesium sulfate), non-steroidal anti-inflammatory drugs (e.g., indomethacin) and ethanol are primary phar- macological agents used in the management of preterm labor. These drugs can either stop uterine contraction during a current episode of preterm labor (first line therapy) or maintain uterine quiescence after an acute episode (maintenance therapy). In general, the value of these medications was tempered by a variety of potential maternal and neonatal side effects (Derbent et al., 2011). Beta-2 adrenergic agonists are the cornerstones of toco- lytic agents. However, Witter et al., (2009) illustrated that these agents when given during critical periods of prenatal development, poor neurophysiological and behavioral tera- togenesis can be induced, this may explain the increased risk of autism, psychiatric disorders, poor cognitive, motor functions, and school performance changes in blood pressure Electronic supplementary material The online version of this article (doi:10.1007/s00044-014-1066-1) contains supplementary material, which is available to authorized users. G. A. R. Y. Suaifan (&)  M. B. Shehadeh  H. A. N. Al-Ijel  M. O. Taha Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan e-mail: gh.suaifan@ju.edu.jo; ghadeer_petra@yahoo.com G. A. R. Y. Suaifan  M. O. Taha Drug Discovery Unit, Faculty of Pharmacy, The University of Jordan, Amman, Jordan K. T. Al-Jamal Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK 123 Med Chem Res (2014) 23:5102–5109 DOI 10.1007/s00044-014-1066-1 MEDICINAL CHEMISTR Y RESEARCH