作者: Baś, Sebastian ; Nitek, Wojciech ; Partyka, Anna ; Handzlik, Jadwiga ; Podlewska, Sabina ; Kucwaj-Brysz, Katarzyna ; Żesławska, Ewa ; Jastrzębska-Więsek, Magdalena ; Wesołowska, Anna ; Satała, Grzegorz

Serotonin 5-HT₇ receptor (5-HT₇R), one of the most recently discovered members of the serotonergic system, has become a promising target in the search for central nervous system disorders. Despite the number of preclinical results, none of the selective 5-HT₇R agents has been approved; therefore, the clinical significance of this protein has not been confirmed yet. Recently, we described very promising, selective, and highly potent hydantoin-derived 5-HT₇R antagonists with confirmed antidepressant activity in vivo and a very good ADMET profile; however, they have been tested in behavioral studies as racemates. In this work, the synthesis of optically pure hydantoin-derived 5-HT₇R agents using cost-effective, classical methods has been presented for the first time. X-ray crystallographic analysis confirmed the absolute configuration on both stereogenic centers and allowed for the elucidation of the mechanism of introduction of epichlorohydrin into the hydantoin N3-position. The radioligand binding results showed a clear configuration preference for 5-HT₇R affinity. The molecular modeling results further indicated the key interaction responsible for lower affinity (with amino acid I3 × 29). Finally, the comparison of the antidepressant and anxiolytic effects of racemates versus stereoisomers suggests an influence of additional, apart from the action on 5HT₇R, factors responsible for the activity in vivo, which is worthy of deeper insight within further studies.

2024-09-01·Journal of Clinical Psychopharmacology

Lack of Efficacy of JNJ-18038683 on Cognitive Impairment in Patients With Stable Bipolar Disorder

Article

作者: Nasr, Suhayl ; Meltzer, Herbert Y. ; Jayathilake, Karu ; Arshadi, Mahdi ; Rassnick, Stefanie ; Drevets, Wayne C. ; Ford, Lisa ; Elmaadawi, Ahmed Z.

BackgroundThe serotonin type 7 (5-HT7) receptor is one of 14 5-HT receptors. It has received attention for its possible role in mood disorders and cognition. The 5-HT7 receptor antagonist, JNJ-18038683, has been reported to be effective in rodent models of depression and REM sleep. Also, 5-HT7 receptor blockade has been postulated to be a key component of cognitive enhancement in a number of drugs. Bipolar disorder (BD) usually endures cognitive impairment (CI); however, no treatment for CI in BD has been approved. This study aimed to evaluate the efficacy of JNJ-18038683 to improve the CI of BD compared to a placebo.MethodsWe conducted a placebo-controlled, 8-week trial of JNJ-18038683 in BD patients. Each patient's data were analyzed and reassessed blindly with a comprehensive neuropsychological battery, depression and hypomania ratings, and overall social and work function measures.ResultsOf 60 patients, 38 (63%) were female, 43 (72%) had BD type 1, and most patients were Caucasian and married. The overall time effect for the combined group shows statistically significant improvement from baseline to week 8 for most of the neurocognitive battery measures. This indicates a significant improvement in psychopathology and cognition during the study time in both JNJ-18038683 and placebo groups, but no difference between groups.ConclusionsThis study showed no efficacy for the improvement of CIBD or mood symptoms with JNJ-18038683 compared to the placebo.

2024-07-01·Toxicology Letters

Effects of psilocin and psilocybin on human 5-HT4 serotonin receptors in atrial preparations of transgenic mice and humans

Article

作者: Hofmann, Britt ; Azatsian, Karyna ; Neumann, Joachim ; Gergs, Ulrich ; Dimov, Kiril

Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT₄ receptor (5-HT₄-TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT₄-TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT₄-TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10 µM were smaller than that of 1 µM 5-HT on the left and right atria from 5-HT₄-TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10 µM psilocybin and psilocin were abrogated by 10 µM tropisetron or by 1 µM GR125487, a more selective 5-HT₄ receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT₄ receptors.

100 项与 5-HT7 receptor antagonists(Egis Gyógyszergyár Zrt) 相关的药物交易

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