Stevan Pecic

Publications (8) View all

• Article: Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors.

  Stevan Pecic, Svetlana Pakhomova, Marcia E Newcomer, Christophe Morisseau, Bruce D Hammock, Zhengxiang Zhu, Alison Rinderspacher, Shi-Xian Deng
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  ABSTRACT: A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.
  Bioorganic & medicinal chemistry letters 12/2012; · 2.65 Impact Factor
• Article: Design, synthesis and evaluation of non-urea inhibitors of soluble epoxide hydrolase.

  Stevan Pecic, Shi-Xian Deng, Christophe Morisseau, Bruce D Hammock, Donald W Landry
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  ABSTRACT: Inhibition of soluble epoxide hydrolase (sEH) has been proposed as a new pharmaceutical approach for treating hypertension and vascular inflammation. The most potent sEH inhibitors reported in literature to date are urea derivatives. However, these compounds have limited pharmacokinetic profiles. We investigated non-urea amide derivatives as sEH inhibitors and identified a potent human sEH inhibitor 14-34 having potency comparable to urea-based inhibitors.
  Bioorganic & medicinal chemistry letters 10/2011; 22(1):601-5. · 2.65 Impact Factor
• Article: Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations.

  Stevan Pecic, Marie A McAnuff, Wayne W Harding
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  ABSTRACT: Nantenine, as well as a number of flexible analogs, were evaluated for acetylcholinesterase (AChE) inhibitory activity in microplate spectrophotometric assays based on Ellman's method. It was found that the rigid aporphine core of nantenine is an important structural requirement for its anticholinesterase activity. Nantenine showed mixed inhibition kinetics in enzyme assays. Molecular docking experiments suggest that nantenine binds preferentially to the catalytic site of AChE but is also capable of interacting with the peripheral anionic site (PAS) of the enzyme, thus accounting for its mixed inhibition profile. The aporphine core of nantenine may thus be a useful template for the design of novel PAS or dual-site AChE inhibitors. Inhibiting the PAS is desirable for prevention of aggregation of the amyloid peptide Aβ, a major causative factor in the progression of Alzheimer's disease (AD).
  Journal of Enzyme Inhibition and Medicinal Chemistry 02/2011; 26(1):46-55. · 1.62 Impact Factor
• Article: Affinity of aporphines for the human 5-HT2A receptor: insights from homology modeling and molecular docking studies.

  Stevan Pecic, Pooja Makkar, Sandeep Chaudhary, Boojala V Reddy, Hernan A Navarro, Wayne W Harding
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  ABSTRACT: Analogs of nantenine were docked into a modeled structure of the human 5-HT(2A) receptor using ICM Pro, GLIDE, and GOLD docking methods. The resultant docking scores were used to correlate with observed in vitro apparent affinity (K(e)) data. The GOLD docking algorithm when used with a homology model of 5-HT(2A), based on a bovine rhodopsin template and built by the program MODELLER, gives results which are most in agreement with the in vitro results. Further analysis of the docking poses among members of a C1 alkyl series of nantenine analogs, indicate that they bind to the receptor in a similar orientation, but differently than nantenine. Besides an important interaction between the protonated nitrogen of the C1 alkyl analogs and residue Asp155, we identified Ser242, Phe234, and Gly238 as key residues responsible for the affinity of these compounds for the 5-HT(2A) receptor. Specifically, the ability of some of these analogs to establish a H-bond with Ser242 and hydrophobic interactions with Phe234 and Gly238 appears to explain their enhanced affinity as compared to nantenine.
  Bioorganic & medicinal chemistry 08/2010; 18(15):5562-75. · 2.82 Impact Factor
• Article: Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.

  Onica Legendre, Stevan Pecic, Sandeep Chaudhary, Sarah M Zimmerman, William E Fantegrossi, Wayne W Harding
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  ABSTRACT: The naturally occurring aporphine alkaloid nantenine, has been shown to antagonize behavioral and physiological effects of MDMA in mice. We have synthesized (+/-)-nantenine via an oxidative cyclization reaction with PIFA and evaluated its binding profile against a panel of CNS targets. To begin to understand the importance of the chiral center of nantenine with regards to its capacity to antagonize the effects of MDMA in vivo, (R)- and (S)-nantenine were prepared and evaluated in a food-reinforced operant task in rats. Pretreatment with either nantenine enantiomer (0.3mg/kg ip) completely blocked the behavioral suppression induced upon administration of 3.0mg/kg MDMA. (+/-)-Nantenine displayed high affinity and selectivity for the alpha(1A) adrenergic receptor among several other receptors suggesting that this alpha(1) subtype may be significantly involved in the anti-MDMA effects of the enantiomers.
  Bioorganic & medicinal chemistry letters 11/2009; 20(2):628-31. · 2.65 Impact Factor