JP-1302: a new tool to shed light on the roles of α2C-adrenoceptors in brain
Autor: | M D, Tricklebank |
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Jazyk: | angličtina |
Rok vydání: | 2007 |
Předmět: |
Central Nervous System
Male Reflex Startle Hypothermia In Vitro Techniques Motor Activity Binding Competitive Piperazines Animals Genetically Modified Rats Sprague-Dawley Mice Radioligand Assay Vas Deferens Receptors Adrenergic alpha-2 Animals Humans Rats Wistar Adrenergic alpha-Antagonists Swimming Brain Chemistry Dose-Response Relationship Drug Cell Membrane Muscle Smooth Research Papers Antidepressive Agents Electric Stimulation Rats Commentary Acridines Adrenergic alpha-Agonists Dexmedetomidine Muscle Contraction |
Popis: | Pharmacological validation of novel functions for the alpha2A-, alpha2B-, and alpha2C-adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ligands. The current study describes a novel highly selective alpha2C-adrenoceptor antagonist, JP-1302 (acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine).Standard in vitro binding and antagonism assays were employed to demonstrate the alpha2C-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 alpha2C-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls.JP-1302 displayed antagonism potencies (KB values) of 1,500, 2,200 and 16 nM at the human alpha2A-, alpha2B-, and alpha2C-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 alpha2-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize alpha2-agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, alpha2-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the alpha2A-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit.The results provide further support for the hypothesis that specific antagonism of the alpha2C-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders. |
Databáze: | OpenAIRE |
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