ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia

Abstract

We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in cAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics.

Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats

“…These patterns of tissue localization suggest the involvement of this receptor in a proportion of psychiatric disorders. We recently observed that a novel 5-HT 5A antagonist ligand attenuated cognitive dysfunction in several animal models of schizophrenia (7). In the present study, we evaluated the effects of novel 5-HT 5A antagonists on cognitive dysfunction associated with dementia such as the cholinergic deficit and aged rat models.…”

“…Substantial evidence has implicated changes in PFC monoamine signaling in age-related working passive avoidance learning (26,27). In a recent immunohistochemistry study, we observed that 5-HT 5A receptors are co-expressed on DA neurons (tyrosine hydroxylase-positive) in the ventral tegmental area (VTA) (7). We therefore hypothesize that 5-HT 5A receptor antagonists block inhibitory 5-HT 5A receptors on DA neurons in the VTA, which enables projection to the mPFC and thereby improves cognitive impairment by activating DA neurons in the mPFC.…”

“…We recently demonstrated that the novel 5-HT 5A antagonist ASP5736 ameliorated positive symptoms and cognitive impairment in animal models of schizophrenia (7).…”

The serotonergic system and cognitive function

“…A preclinical study demonstrated that blocking and stimulation of 5-HTR5A might impair and facilitate short- and long-term memory, respectively [ 150 ]. On the other hand, the 5-HTR5A antagonist ASP5736 improved positive and cognitive symptoms in a schizophrenia mouse model as well as in aged rats and mice with scopolamine-induced working memory deficit [ 151 , 152 ]. These data suggest that ASP5736 may be used in the treatment of cognitive defects in schizophrenic patients.…”

Serotonin, neural markers, and memory

“…Of course further investigation is necessary, meanly with selective 5-HT 5A compounds (Gonzalez et al, 2013 ). Interestingly, Yamazaki et al ( 2014 , 2015 ) reported that a 5-HT 5A receptor antagonist ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia and in aged rats and induced-amnesia. An analogous case is observed regarding 5-HT 1A partial agonists (see above).…”