| Autor: |
Sturchler, Emmanuel, Li, Xia, de Lourdes Ladino, Maria, Kaczanowska, Kasia, Cameron, Michael, Griffin, Patrick R, Finn, MG, Markou, Athina, McDonald, Patricia |
| Rok vydání: |
2017 |
| Předmět: |
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| Zdroj: |
Pharmacology research & perspectives, vol 5, iss 2 |
| Popis: |
Positive modulation of the GABAB receptor (GABABR) represents a potentially useful therapeutic approach for the treatment of nicotine addiction. The positive allosteric modulators (PAMs) of GABABR GS39783 and BHF177 enhance GABA-stimulated [35S]GTP γS-binding, and have shown efficacy in a rodent nicotine self-administration procedure reflecting aspects of nicotine dependence. Interestingly, the structural related analog, NVP998, had no effect on nicotine self-administration in rats despite demonstrating similar pharmacokinetic properties. Extensive in vitro characterization of GS39783, BHF177, and NVP998 activity on GABABR-regulated signaling events, including modulation of cAMP, intracellular calcium levels, and ERK activation, revealed that these structurally related molecules display distinct pathway-specific signaling activities that correlate with the dissimilarities observed in rodent models and may be predictive of in vivo efficacy. Furthermore, these GABABR allosteric modulators exhibit species-dependent activity. Collectively, these data will be useful in guiding the development of GABABR allosteric modulators that display optimal in vivo efficacy in a preclinical model of nicotine dependence, and will identify those that have the potential to lead to novel antismoking therapies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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