Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

Matsuda, Takehisa; Yoshikawa, Takashi; Suzuki, Makoto; Asano, Shoichi; Somboonthum, Pranee; Takuma, Kazuhiro; Nakano, Yukiko I.; Morita, Tomoko; Nakasu, Yukiko; Kim, Hye Sun; Egawa, Mitsuo; Tobe, Akihiro; Baba, Akemichi

doi:10.1254/jjp.69.357

Cited by 53 publications

(32 citation statements)

References 39 publications

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“…The net effect of diminished cell firing (and consequently diminished 5-HT release) and functional postsynaptic receptor antagonism is a reduction in serotonergic tone to the SCN. The same is true for MKC-242, although this compound may display greater agonist properties in the agonistpartial agonist-antagonist continuum (Matsuda et al, 1995). Interestingly, both compounds also share the ability to block alpha-1 adrenergic receptors; at the level of the raphe nuclei, this action too can reduce cell firing by removing excitatory noradrengic tone (Baraban and Aghajanian, 1980).…”

Section: Discussionmentioning

confidence: 93%

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

2008

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Health problems can arise from de-synchrony between the external environment and the endogenous circadian rhythm, yet the circadian system is not able to quickly adjust to large, abrupt changes in the external daily cycle. In this study, we investigated the ability of to potentiate the circadian rhythm response to light as measured by phase of behavioral activity rhythms. (5 mg/kg, i.p.) was able to significantly potentiate the response to light both in dark-adapted and entrained hamsters. Furthermore, was effective even when administered up to 6 hours after light onset. Response to a light pulse was both greater in magnitude and involved fewer unstable transient cycles. Finally, was able to speed re-entrainment to a 6 h advance of the light: dark cycle by an average of 6 days when compared to vehicle-treated animals. This work suggests that compounds like NAN-190 may hold great potential as a pharmaceutical treatment for jetlag, shift work, and other circadian disorders. Keywordsserotonin; circadian; light; rhythm; jet-lag; phase shift; transient; entrainment Circadian rhythms are endogenously generated rhythms that coordinate processes such as hormone release, digestive enzyme secretion, and the sleep/wake cycle. In mammals, the major pacemaker is located in the suprachiasmatic nucleus (SCN) in the brain, which uses environmental cues to synchronize, or entrain, internal rhythms to the external surroundings (Rusak and Zucker, 1979; Ralph et al., 1990). Jetlag occurs when internal circadian rhythms become desynchronized from the external time. In humans, this desynchronization results in acute negative effects such as lowered performance levels on the job, difficulty sleeping at the appropriate times, and gastrointestinal problems. If frequent or prolonged, circadian desynchrony may be associated with more chronic health problems in people such as increased risk of breast cancer, cardiovascular disease, reproductive difficulties and peptic ulcers (Knutsson, 2003;Megdal et al., 2005). Studies using laboratory animals even link jetlag with increased rate of tumor growth and increased mortality in aged mice (Davidson et al., 2006;Filipski et al., 2004). Given the detrimental effects, studies have investigated several different methods to reduce circadian desynchrony. Melatonin, exposure to bright light, and gradual shifting of the sleep/wake cycle prior to jet travel in varying combinations have all been shown *Corresponding author. Tel: 1-413-585-3925; fax: 1-413-585-3786. E-mail address: mharring@email.smith.edu (M. Harrington). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the ...

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Section: Discussionmentioning

confidence: 93%

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

2008

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“…Isolation rearing-induced aggression has been proposed to be useful as an animal model for assessing benzodiazepine and non-benzodiazepine anxiolytic activities. We have found that the selective 5-HT 1A receptor agonist osemozotan (previously called as MKC-242) (3,15) as well as the g-aminobutyric acid A (GABA A )-receptor agonist diazepam reduced isolation-induced aggressive behavior (16,17). The antiaggressive effect of osemozotan was observed at low doses, suggesting the involvement of presynaptic 5-HT 1A receptor activation (6).…”

Section: Aggressive Behaviorsmentioning

confidence: 99%

The Potential Role of Serotonin1A Receptors in Post-weaning Social Isolation–Induced Abnormal Behaviors in Rodents

2014

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Abstract. Post-weaning social isolation in mice induces behavioral abnormalities such as hyperactivity, aggression, depression-and anxiety-like behaviors, deficits of prepulse inhibition, and reduced pain sensitivity to the noxious stimuli. Then, this mouse is considered to be a model of psychiatric disorders including schizophrenia. We have found that serotonin (5-HT) 1A -receptor ligands attenuate these abnormalities, suggesting the pharmacological role of the receptor in treatment of psychiatric disorders. Furthermore, we have recently found that isolation-reared mice show social encounter-induced hyperactivity, a novel phenotype of the abnormal behaviors, and the hyperactivity is triggered by activation of the serotonergic system from the dorsal raphe to the frontal cortex. This review summarizes the effects of 5-HT 1A receptor ligands on aggressive behavior, deficits of prepulse inhibition, reduced pain sensitivity to the noxious stimuli, and encounter-induced hyperactivity in social isolation-reared mice. These findings suggest that the 5-HT 1A receptor is a potential target molecule for treatment of psychiatric disorders and pain.

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“…Evidence has accumulated to indicate that the 5-HT 2A -and 5-HT 1A -receptor activation in the hypothalamus mediate the hyperthermic and hypothermic action, respectively, in rats (8,9). This raises the hypothesis that puerarin acts through a 5-HT 2A -and / or 5-HT 1A -receptor mechanism to exert its thermal effect.…”

Section: Introductionmentioning

confidence: 99%

Puerarin Acts Through Brain Serotonergic Mechanisms to Induce Thermal Effects

Chueh¹,

Chang

Chio

et al. 2004

J Pharmacol Sci

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Abstract. The present study was attempted to investigate the effect of puerarin, an isoflavone compound isolated from Pueraria lobata, on both the basal body temperature and pyrogenic fever in unanesthetized, restrained rats. Intraperitoneal administration of puerarin or crude extracts of Pueraria lobata elicited hypothermia. Direct administration of a small amount of puerarin into the lateral cerebral ventricle produced the same extent of hypothermia. Systemic or central administration of puerarin causes a decrease in both colonic temperature and hypothalamic 5-HT efflux in rats. The puerarin-induced hypothermia and decreased 5-HT efflux in the hypothalamus were attenuated by selective depletion of hypothalamic 5-HT produced by intracerebroventricular injection of 5,7-dihydroxytryptamine. Furthermore, the puerarin-induced hypothermia was almost completely abolished by treatment with a 5-HT 2A -receptor agonist (DOI or quipazine) or a 5-HT 1A -receptor antagonist [(-)-pindolol]. A 5-HT 2A -receptor antagonist (ketanserin) or a 5-HT 1A -receptor agonist (8-OH-DPAT) had additive effects with puerarin. Intracerebroventricular administration of interleukin-1 caused an increase in both colonic temperature and hypothalamic 5-HT efflux. The interleukin-1-induced hyperthermia and increased 5-HT efflux in the hypothalamus were attenuated by treatment with systemic administration of puerarin. The data indicate that puerarin exerts its hypothermic and antipyretic effects by activating 5-HT 1A receptor and / or antagonizing 5-HT 2A receptors in the hypothalamus.

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Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

Cited by 53 publications

References 39 publications

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

NAN-190 potentiates the circadian response to light and speeds re-entrainment to advanced light cycles

The Potential Role of Serotonin1A Receptors in Post-weaning Social Isolation–Induced Abnormal Behaviors in Rodents

Puerarin Acts Through Brain Serotonergic Mechanisms to Induce Thermal Effects

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