Author: Watanabe, Takehiko ; Okamura, Nobuyuki ; Yoshikawa, Takeo ; Nakamura, Tadaho ; Yanai, Kazuhiko ; Miura, Yamato ; Mohsen, Attayeb ; Harada, Ryuichi ; Shibuya, Katsuhiko ; Iida, Tomomitsu ; Naganuma, Fumito

Histaminergic neurons are activated by histamine H(3) receptor (H(3)R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H(3)R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H(3)R-mediated behavioural changes using a specific H(3)R antagonist, JNJ-10181457 (JNJ). First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased N(τ)-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines. Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by α-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H(3)R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H(1)R gene knockout mice but not in histamine H2 receptor (H(2)R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an H(1)R antagonist, and dominantly by zolantidine, an H(2)R antagonist. These results suggest that H(3)R blockade induces histamine release, activates H(2)R and elicits exploratory locomotor activity and anxiety-like behaviours.

01 Nov 2011·Brain ResearchQ4 · MEDICINE

The CRH-R1 receptor mediates luteinizing hormone, prolactin, corticosterone and progesterone secretion induced by restraint stress in estrogen-primed rats

Q4 · MEDICINE

Article

Author: Traslavina, Guillermo A. Ariza ; Franci, Celso Rodrigues

Acute stress has been shown to modify hypothalamus-pituitary-gonadal (HPG) axis activity. Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamus-pituitary-adrenal (HPA) axis, has been implicated as a mediator of stress-induced effects on the reproductive axis. The role of the specific CRH receptor subtypes in this response is not completely understood. In the current study, we investigated the role of the CRH-R(1) receptor on luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), progesterone (P) and corticosterone (CT) secretion in stress-induced responses under the influence of estrogen (E(2)). Estrogen-primed ovariectomized rats (estradiol cypionate, 10 μg sc) received an i.v. administration of antalarmin (0.1 or 1mg/kg), a selective CRH-R(1) antagonist, or vehicle before restraint stress for 40 min. Seven blood samples were collected from two experimental groups (one from 10:00 h to 14:00 h and the other from 10:00 h to 18:00 h). An increase of plasma LH induced by restraint acute-stress was followed by alteration of the secretion pattern in the estrogen-induced afternoon surge. In a similar manner, we observed a suppression of the afternoon surge in plasma FSH, a delay of E(2)-induced PRL secretion, and an increase in plasma P and CT. Antalarmin attenuated stress-induce LH increase, decreased CT and P secretion and blocked the stress effects on PRL secretion. These findings suggest that CRH-R(1) mediates, at least in part, the restraint stress effects on the HPA, PRL, and reproductive axes.

01 May 2006·Current Medicinal ChemistryQ2 · MEDICINE

Recent Advances in Small Molecule Antagonists of the Corticotropin- Releasing Factor Type-1 Receptor-Focus on Pharmacology and Pharmacokinetics

Q2 · MEDICINE

Review

Author: Chen, C

Corticotropin-releasing factor (CRF), a 41-amino acid peptide, has been recognized as an important factor mediating stress. Efforts to discover small molecule antagonists of the CRF type-1 receptor (CRF(1)-R) for potentially novel treatment of anxiety and depression started in the early 1990's. Although highly potent in vitro and efficacious in animal models, early reported compounds such as CP-154,526 and NBI-27914 are highly lipophilic and possess high plasma protein and tissue binding, long elimination half life, and toxicity, likely due in part to accumulation in tissues. Recently, several laboratories have reported potent CRF(1)-R antagonists with improved physicochemical properties. Compounds such as DMP696, NBI-30775/R121919 and R278995/CRA0450 possess at least one additional polar group in their structures and are therefore less lipophilic than the earlier compounds, while still maintaining high potency. For example, DMP696 has a K(i) value of 1.7 nM and a cLogP of 3.2, which is similar to CP-154,526 in potency but about 4-log units lower in partition coefficient. Despite its high plasma protein binding (98.5% in rat), DMP696 occupies over 50% of brain CRF(1)-R at a total plasma concentration above 100 nM, which is consistent with the doses that produce anxiolytic effects in the rat defense withdrawal test of anxiety. This article will review small molecule CRF(1)-R antagonists by focusing on their pharmacological and pharmacokinetic properties. In addition, the pharmacology of small molecules binding to the CRF(1) receptor will be discussed. An orally available compound with desirable properties in these categories will have a good chance to be developed into a novel treatment for anxiety and depression which may be devoid of the side effects of existing antidepressant treatments.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Duquesne University of The Holy Spirit	05 Aug 2011

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