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 84
- Downloads 0
Transfection efficiency and toxicity of polyethylenimine in differentiated Calu-3 and nondifferentiated COS-1 cell cultures
In the present study, we evaluated polyethylenimine (PEI) of different molecular weights (MWs) as a DNA complexing agent for its efficiency in transfecting nondifferentiated COS-1 (green monkey fibroblasts) and well-diff...
Commentary: Drug hypersensitivity—Where do we stand?
Impact of Data Base Structure in a Successful In Vitro-In Vivo Correlation for Pharmaceutical Products
The in vitro-in vivo correlation (IVIVC) (Food and Drug Administration 1997) aims to predict performances in vivo of a pharmaceutical formulation based on its in vitro characteristics. It is a complex process that (i) in...
An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1
Efflux transporters of the ATP-binding cassette superfamily including breast cancer resistance protein (Bcrp/Abcg2), P-glycoprotein (P-gp/Abcb1) and multidrug resistance-associated proteins (Mrp’s/Abcc’s)...
Drug Discovery and Regulatory Considerations for Improving In Silico and In Vitro Predictions that Use Caco-2 as a Surrogate for Human Intestinal Permeability Measurements
There is a growing need for highly accurate in silico and in vitro predictive models to facilitate drug discovery and development. Results from in vitro permeation studies across the Caco-2 cell monolayer are commonly us...