Background and purpose: Pharmacological validation of novel functions for the a 2A -, a 2B -, and a 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 a 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 a 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 a 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 (K B values) of 1,500, 2,200 and 16 nM at the human a 2A -, a 2B -, and a 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 a 2 -subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize a 2 -agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, a 2 -agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the a 2A -adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCPinduced prepulse-inhibition deficit. Conclusions and implications:The results provide further support for the hypothesis that specific antagonism of the a 2C -adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.

Starting from two acridine compounds identified in a high-throughput screening campaign (1 and 2, Table 1), a series of 4-aminoquinolines was synthesized and tested for their properties on the human alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)). A number of compounds with good antagonist potencies against the alpha(2C)-adrenoceptor and excellent subtype selectivities over the other two subtypes were discovered. For example, (R)-{4-[4-(3,4-dimethylpiperazin-1-yl)phenylamino]quinolin-3-yl}methanol 6j had an antagonist potency of 8.5 nM against, and a subtype selectivity of more than 200-fold for, the alpha(2C)-adrenoceptor. Investigation of the structure-activity relationship identified a number of structural features, the most critical of which was an absolute need for a substituent in the 3-position of the quinoline ring. The 3-position on the piperazine ring was also found to play an appreciable role, as substitutions in that position exerted a significant and stereospecific beneficial effect on the alpha(2C)-adrenoceptor affinity and potency. Replacing the piperazine ring proved difficult, with 1,4-diazepanes representing the only viable alternative.