Pharmacological characterization and CNS effects of a novel highly selective alpha2C-adrenoceptor antagonist JP-1302.
Br J Pharmacol
; 150(4): 391-402, 2007 Feb.
Article
en En
| MEDLINE
| ID: mdl-17220913
ABSTRACT
BACKGROUND AND PURPOSE:
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). EXPERIMENTALAPPROACH:
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. KEYRESULTS:
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. CONCLUSIONS AND IMPLICATIONS 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperazinas
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Acridinas
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Sistema Nervioso Central
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Receptores Adrenérgicos alfa 2
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Antagonistas Adrenérgicos alfa
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Br J Pharmacol
Año:
2007
Tipo del documento:
Article
País de afiliación:
Finlandia