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- Title
Pharmacological characterization and CNS effects of a novel highly selective α<sub>2C</sub>-adrenoceptor antagonist JP-1302.
- Authors
Sallinen, J; Höglund, I; Engström, M; Lehtimäki, J; Virtanen, R; Sirviö, J; Wurster, S; Savola, J-M; Haapalinna, A
- Abstract
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 (K B 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.British Journal of Pharmacology (2007) 150, 391–402. doi:10.1038/sj.bjp.0707005; published online 15 January 2007
- Subjects
ADRENERGIC receptors; DRUG receptors; SYMPATHETIC nervous system; MEDICAL sciences; PHARMACOLOGY
- Publication
British Journal of Pharmacology, 2007, Vol 150, Issue 4, p391
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0707005