Article date: February 2007
By: J Sallinen, I Höglund, M Engström, J Lehtimäki, R Virtanen, J Sirviö, S Wurster, J‐M Savola, A Haapalinna in Volume 150, Issue 4, pages 391-402
Background and purpose:
Pharmacological validation of novel functions for the α2A‐, α2B‐, and α2C‐adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype‐selectivity of available ligands. The current study describes a novel highly selective α2C‐adrenoceptor antagonist, JP‐1302 (acridin‐9‐yl‐[4‐(4‐methylpiperazin‐1‐yl)‐phenyl]amine).
Experimental approach:
Standard in vitro binding and antagonism assays were employed to demonstrate the α2C‐AR specificity of JP‐1302. In addition, JP‐1302 was tested in the forced swimming test (FST) and the prepulse‐inhibition of startle reflex (PPI) model because mice with genetically altered α2C‐adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild‐type controls.
Key results:
JP‐1302 displayed antagonism potencies (KB values) of 1,500, 2,200 and 16 nM at the human α2A‐, α2B‐, and α2C‐adrenoceptor subtypes, respectively. JP‐1302 produced antidepressant and antipsychotic‐like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine‐induced PPI deficit. Unlike the α2‐subtype non‐selective antagonist atipamezole, JP‐1302 was not able to antagonize α2‐agonist–induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, α2‐agonist‐induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the α2A‐adrenoceptor subtype. In contrast to JP‐1302, atipamezole did not antagonize the PCP‐induced prepulse‐inhibition deficit.
Conclusions and implications:
The results provide further support for the hypothesis that specific antagonism of the α2C‐adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.
DOI: 10.1038/sj.bjp.0707005
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