Pharmacological characterization and CNS effects of a novel highly selective α2C-adrenoceptor antagonist JP-1302

Background and purpose: Pharmacological validation of novel functions for the alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ligands. The current study describes a novel highly selective alpha(2C)-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 alpha(2C)-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 alpha(2C)-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 alpha(2A)-, alpha(2B)-, and alpha(2C)-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 alpha(2)-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize alpha(2)-agonist-induced sedation ( measured as inhibition of spontaneous locomotor activity), hypothermia, alpha(2)-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the alpha(2A)-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 alpha(2C)-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.