The irritable bowel syndrome (IBS) is a functional gastrointestinal motor and visceral sensation disorder that is more common in women than men. Female serotonin transporter (SERT)-gene knockout (KO) rats exhibit hypersensitivity to colorectal balloon distention (CRD) that mimics colonic hypersensitivity occurring in female IBS patients. Alosetron (5-HT3 receptor antagonist) is used to treat diarrhea-predominant IBS in female patients. Other 5-HT3 receptor antagonists are ineffective at treating IBS symptoms. The visceromotor response (VMR) to CRD in SERT-KO and wild-type (WT) rats was measured following subcutaneous (sc), intracerobroventricular (icv), or intrathecal (it) treatment with 5-HT3 receptor antagonists and an agonist. Alosetron (sc) and granisetron (antagonists) caused a paradoxical increase in the VMR to CRD in SERT-KO female rats. Alosetron (sc) increased the VMR to CRD in WT male rats. Alosetron (it) increased the VMR to CRD in SERT-KO female rats only, and the 5-HT3 receptor agonist SR-52772 increased the VMR to CRD in SERT-KO male rats. Depletion of spinal 5-HT using 5,7-dihydroxytryptamine prevented the increase in VMR to CRD in SERT-KO female and male rats treated it with alosetron and SR-52772, respectively. Alosetron (icv) did not affect the VMR to CRD in WT or KO female rats, but it increased the VMR in male SERT-KO but not WT male rats. These data suggest that 5-HT3 receptor signaling at the dorsal spinal cord mediates visceral hypersensitivity in female SERT-KO rats. Such differences could facilitate development of sex-specific drug treatments for visceral pain. NEW & NOTEWORTHY We studied a model of female sex-specific visceral hypersensitivity using rats that had a loss of function of the serotonin transporter (SERT) caused by gene truncation. Female SERT-KO rats exhibited visceral hypersensitivity in response to colorectal balloon distention. We found that increased 5-HT signaling at dorsal spine 5-HT3 receptors was responsible for visceral hypersensitivity in female but not male SERT-KO rats.
Inactivators of plasminogen activator inhibitor-1 (PAI-1) have been identified as possible treatments for a range of conditions, including atherosclerosis, venous thrombosis, and obesity. We describe the synthesis and inhibitory activity of a novel series of compounds based on bis-arylsulfonamide and aryl sulfonimide motifs that show potent and specific activity towards PAI-1. Inhibitors containing short linking units between the sulfonyl moieties and a 3,4-dihydroxy aryl substitution pattern showed the most potent inhibitory activity, and retained high specificity for PAI-1 over the structurally-related serpin anti-thrombin III (ATIII). Keywords PAI-1 inhibitors; bis-arylsulfonamide; aryl sulfonimidePlasminogen activator inhibitor-1 (PAI-1) is member of the serpin superfamily of protease inhibitors and is the primary inhibitor of urokinase type plasminogen activator (uPA) and tissue type plasminogen activator (tPA). 1 At normal physiologic levels PAI-1 plays a significant role in multiple processes, including fibrinolysis, angiogenesis, cell migration, and wound healing. [2][3][4][5][6] Pathologic levels of PAI-1 have been connected with obesity and metabolic syndrome, tumor metastasis, and vascular diseases such as venous thrombosis and atherosclerosis, making it an attractive pharmacological target. 7-13 However, PAI-1 has proven to be a challenging target for drug design as it is present in multiple conformational forms and has a flexible reactive center loop. Despite the challenges inherent in the development of small-molecule PAI-1 inactivators, several have been reported recently, although each has drawbacks that have impeded further progress in their development. [14][15][16][17][18][19][20][21][22] The most studied of these inhibitors, tiplaxtinin, 3,19,[23][24][25][26] Supplementary material containing synthetic details, spectroscopic characterization of novel compounds, and assay conditions for this paper is available to all readers.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 journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2011 February 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHere we report the development of a novel class of PAI-1 inhibitors based on an aryl sulfonamide or aryl sulfonimide motif that shows up to 30-fold more potent inhibitory activity toward PAI-1 than that of tiplaxtinin. Based on insights gained from a screen for anti-PAI-1 activity of a library of structurally diverse compounds, 27 we developed a set of compounds designed to probe structural requi...
No abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.