Abstract
Drug and Alcohol Dependence 156 (2015) e183–e245 e245 OX1/OX2 receptor antagonist ACT-078573 and the OX2 selective antagonist TCS-OX2-29. Aimed at elucidating SAR requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogs bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. Methods: All target compounds were synthesized and characterized by MS, NMR and HPLC. Target compounds were evaluated in calcium-dependent functional assays in RD-HGA16 (Molecular Devices) cell lines stably expressing either theOX1orOX2 receptor. Results: The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified.When combinedwith structuralmodifications thatwere previously found to improve selectivity, we have identified compounds with apparent dissociation constants (Ke) less than 20nM at theOX1 receptor and >500-fold selectivity over theOX2 receptor. In vivo, select compounds blocked the development of locomotor sensitization to cocaine in rats. Conclusions: These findings will expedite the development of potent and selective OX1 antagonists as medications for the treatment of OX1-mediated disorders such as drug addiction. Financial support: NIH grants DA032837, DA026582 and DA034806. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.659 Effects of environmental enrichment on microRNA-221 expression and ERK phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self-administration Jun Zhu1,2,∗, Adrian M. Gomez1, Wei-lun Sun1, Diego Altomare1, Kim E. Creek1, Steven B. Harrod2 1 Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, United States 2 Psychology, University of South Carolina, Columbia,
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