更新于：2024-11-21

5-HT2 receptor antagonists and 5-HT7 receptor agonists(Janssen)

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

靶点

5-HT2 receptor x 5-HT7 receptor

作用机制

5-HT2 receptor拮抗剂(5-羟色胺2受体拮抗剂)、5-HT7 receptor激动剂(5-羟色胺受体7激动剂)

治疗领域-

在研适应症-

非在研适应症-

原研机构

Janssen, Inc.

在研机构

Janssen, Inc.

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C16H20FN3

InChIKeyRBYJHELKTYHZNG-UHFFFAOYSA-N

CAS号851375-22-9

关联

100 项与 5-HT2 receptor antagonists and 5-HT7 receptor agonists(Janssen) 相关的临床结果

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100 项与 5-HT2 receptor antagonists and 5-HT7 receptor agonists(Janssen) 相关的转化医学

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100 项与 5-HT2 receptor antagonists and 5-HT7 receptor agonists(Janssen) 相关的专利（医药）

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项与 5-HT2 receptor antagonists and 5-HT7 receptor agonists(Janssen) 相关的文献（医药）

2025-01-01·The Journal of Pain

Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain

Article

作者: Sluka, Kathleen A ; Lesnak, Joseph B ; Rasmussen, Lynn ; Lesnak, Joseph B. ; Plumb, Ashley N ; Plumb, Ashley N. ; Sluka, Kathleen A.

Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression. Since prior studies show testosterone protects from the development of widespread pain, and females have widespread pain in the activity-induced pain model, we hypothesized that testosterone modulates serotonin signaling to enhance analgesia in female mice with widespread pain. We showed that testosterone reduced the enhanced SERT protein expression and increased 5-HT_2A receptor mRNA expression in the RVM normally observed in the activity-induced pain model in females, but not males. Inhibition of SERT in the RVM was analgesic in both female and male mice; this analgesia was blocked by co-administration of 5-HT_2A antagonist. Next, using in situ hybridization, we demonstrated co-expression of SERT, 5-HT_2A receptor, and androgen receptor mRNA in cells within the RVM in female mice. Lastly, activation of androgen receptors using dihydrotestosterone reduced hyperalgesia in female mice. These data therefore show for the first time expression of androgen receptors in the RVM in female mice, that activation of androgen receptors reduces nociceptive behaviors, and endogenous testosterone modulates SERT and 5-HT2 receptor expression. Thus, we show a sex-specific role for how testosterone modulates analgesia in female mice. PERSPECTIVE: This article presents novel mechanisms testosterone's protection against muscle pain in female mice showing modulation of the serotonin system in the rostral ventromedial medulla. Understanding the relationship between testosterone and serotonin could lead to better treatment of individuals with muscle pain.

2024-07-01·Physiological Reports

Serotonin receptor‐mediated vasorelaxation occurs primarily through 5‐HT₄ activation in bovine lateral saphenous vein

Article

作者: Trotta, Ronald J. ; Klotz, James L. ; Harmon, David L.

AbstractTo better understand mechanisms of serotonin‐ (5‐HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5‐HT or selective 5‐HT receptor agonists. Vessels were pre‐contracted with 1 × 10−4 M phenylephrine and exposed to increasing concentrations of 5‐HT or 5‐HT receptor agonists that were selective for 5‐HT1B, 5‐HT2B, 5‐HT4, and 5‐HT7. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre‐contraction. At 1 × 10−7 M 5‐HT, a relaxation was observed with an 88.7% decrease (p < 0.01) from the phenylephrine maximum. At 1 × 10−4 M 5‐HT, a contraction was observed with a 165% increase (p < 0.01) from the phenylephrine maximum. Increasing concentrations of agonists selective for 5‐HT2B, 5‐HT4, or 5‐HT7 resulted in a 27%, 92%, or 44% (p < 0.01) decrease from the phenylephrine maximum, respectively. Of these 5‐HT receptor agonists, the selective 5‐HT4 receptor agonist resulted in the greatest potency (−log EC50) value (6.30) compared with 5‐HT2B and 5‐HT7 receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5‐HT4 in 5‐HT‐mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5‐HT4 antagonist (1 × 10−5 M) for 5‐min prior to the phenylephrine pre‐contraction and 5‐HT additions. Antagonism of the 5‐HT4 receptor attenuated the vasorelaxation caused by 5‐HT. Approximately 94% of the vasorelaxation occurring in response to 5‐HT could be accounted for through 5‐HT4, providing strong evidence that 5‐HT‐mediated vasorelaxation occurs through 5‐HT4 activation in bovine peripheral vasculature.

2019-01-01·International Review of Neurobiology3区 · 医学

5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology

3区 · 医学

Article

作者: Smith, Mark A ; Sharma, Hari Shanker ; Muresanu, Dafin Fior ; Castellani, Rudy J ; Sharma, Aruna ; Dey, Prasanta Kumar

5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150mg/kg) in the plasma and brain associated with profound hyperthermia (+3.86±0.24°C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to ^[131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.

100 项与 5-HT2 receptor antagonists and 5-HT7 receptor agonists(Janssen) 相关的药物交易

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