RT Journal Article
SR Electronic
T1 FTBMT, a novel and selective GPR52 agonist, demonstrates antipsychotic-like and procognitive effects in rodents revealing a potential therapeutic agent for schizophrenia
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.242925
DO 10.1124/jpet.117.242925
A1 Keiji Nishiyama
A1 Hirobumi Suzuki
A1 Toshiya Harasawa
A1 Noriko Suzuki
A1 Emi Kurimoto
A1 Takanori Kawai
A1 Minoru Maruyama
A1 Hidetoshi Komatsu
A1 Kensuke Sakuma
A1 Yuji Shimizu
A1 Masato Shimojo
YR 2017
UL http://jpet.aspetjournals.org/content/early/2017/08/29/jpet.117.242925.abstract
AB GPR52 is a Gs protein-coupled receptor that is predominantly expressed in the striatum and nucleus accumbens, and was recently proposed as a potential therapeutic target in schizophrenia. In the current study, we investigated the in vitro and in vivo pharmacological activities of a novel GPR52 agonist, 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (FTBMT) functioned as a selective GPR52 agonist in vitro and in vivo, as demonstrated by the activation of cAMP signaling in striatal neurons. FTBMT inhibited MK-801-induced hyperactivity (an animal model for acute psychosis) without causing catalepsy in mice. The c-fos expression also revealed that FTBMT preferentially induced neuronal activation in the shell of the nucleus accumbens, compared with the striatum, thereby supporting its pharmacological profile. Furthermore, FTBMT improved recognition memory in a novel object recognition test and attenuated MK-801-induced working memory deficits in a radial arm maze test in rats. These procognitive effects were supported by the results of FTBMT-induced c-fos expression in brain regions related to cognition, including the medial prefrontal cortex, entorhinal cortex, and hippocampus. Taken together, these findings suggest that FTBMT shows antipsychotic and procognitive properties without causing catalepsy in rodents. Given its unique pharmacological profile, which differs from that of current antipsychotics, FTBMT may provide a new therapeutic option for the treatment of positive and cognitive symptoms of schizophrenia.