Synthesis and Pharmacological Characterization of a Novel Sigma Receptor Ligand with Improved Metabolic Stability and Antagonistic Effects Against Methamphetamine
Journal Title: The AAPS Journal - Year 2012, Vol 14, Issue 1
Abstract
Methamphetamine interacts with sigma receptors at physiologically relevant concentrations suggesting a potential site for pharmacologic intervention. In the present study, a previous sigma receptor ligand, CM156, was optimized for metabolic stability, and the lead analog was evaluated against the behavioral effects of methamphetamine. Radioligand binding studies demonstrated that the lead analog, AZ66, displayed high nanomolar affinity for both sigma-1 and sigma-2 receptors (2.4 ± 0.63 and 0.51 ± 0.15, respectively). In addition, AZ66 had preferential affinity for sigma receptors compared to seven other sites and a significantly longer half-life than its predecessor, CM156, in vitro and in vivo. Pretreatment of male, Swiss Webster mice with intraperitoneal (10–20 mg/kg) or oral (20–30 mg/kg) dosing of AZ66 significantly attenuated the acute locomotor stimulatory effects of methamphetamine. Additionally, AZ66 (10–20 mg/kg, i.p.) significantly reduced the expression and development of behavioral sensitization induced by repeated methamphetamine administration. Taken together, these data indicate that sigma receptors can be targeted to mitigate the acute and subchronic behavioral effects of methamphetamine and AZ66 represents a viable lead compound in the development of novel therapeutics against methamphetamine-induced behaviors.
Authors and Affiliations
Michael J. Seminerio, Matthew J. Robson, Ahmed H. Abdelazeem, Christophe Mesangeau, Seshulatha Jamalapuram, Bonnie A. Avery, Christopher R. McCurdy, Rae R. Matsumoto
Keywords
Related Articles
- EP ID EP681186
- DOI 10.1208/s12248-011-9311-8
- Views 83
- Downloads 0
Multidimensional Atomic Force Microscopy: A Versatile Novel Technology for Nanopharmacology Research
The online version of this article (doi:10.1208/s12248-010-9232-y) contains supplementary material, which is available to authorized users.
A combination of iontophoresis and the chelating agent 1, 10 phenanthroline act synergistically as penetration enhancers
The peroxovanadium compound VO(O2)2, 1,10 phenanthroline (bpV (phen)) is capable of lowering blood glucose levels. It is not available in oral form, but it is effective when delivered transdermally. Iontophoresis can sig...
Choice of LC-MS Methods for the Absolute Quantification of Drug-Metabolizing Enzymes and Transporters in Human Tissue: a Comparative Cost Analysis
The online version of this article (doi:10.1208/s12248-014-9712-6) contains supplementary material, which is available to authorized users.
Engineered Nanoparticulate Drug Delivery Systems: The Next Frontier for Oral Administration?
For the past few decades, there has been a considerable research interest in the area of oral drug delivery using nanoparticle (NP) delivery systems as carriers. Oral NPs have been used as a physical approach to improve...
Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases
With the advent of novel and personalized therapeutic approaches for cancer and inflammatory diseases, there is a growing demand for designing delivery systems that circumvent some of the limitation with the current ther...