Design, Synthesis, and Evaluation of Isoquinoline Ureas as TRPV1 Antagonists

2020 ◽  
Vol 16 (2) ◽  
pp. 202-211
Author(s):  
Nehaben A. Gujarati ◽  
Bradley J. Undem ◽  
Vijaya L. Korlipara
Keyword(s):  
Molecular Modeling ◽  
Guinea Pig ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Transient Receptor Potential Vanilloid ◽  
Functional Assay ◽  
Design Synthesis ◽  
Novel Approach ◽  
Transient Receptor

Background: The inhibition of transient receptor potential vanilloid receptor 1 (TRPV1) has emerged as a novel approach for the treatment of various pain states. Pyrrolidinyl urea, SB 705498 with pKb = 7.3 in guinea pig TRPV1 receptor has been investigated in Phase II clinical trials for pain and chronic cough. Another heteroaryl urea derivative, A-425619 1, has been reported to be a potent and selective TRPV1 antagonist of capsaicin-evoked receptor activation with an IC50 value of 4 nM in hTRPV1. Objective: A series of thirteen A-425619 1 analogues with modifications centered around the Cregion were synthesized to understand the binding site characteristics of TRPV1 receptors. Method: We synthesized a series of isoquinoline ureas and evaluated their antagonist potency using smooth muscle assay using guinea pig trachea along with the evaluation of the molecular properties and molecular modeling using CoMFA studies. Results: p-Chloro 4, p-bromo 5, m-isothiocyanate 15, and p-isothiocyanate 16 derivatives were found to be the most potent members of the series with pKb values in the range of 7.3-7.4 in the functional assay using guinea pig trachea. The lead compound A-425619 1 exhibited a pKb value of 8.1 in this assay. Conclusion: The para-substituted analogues were found to be more potent than the ortho- and meta- analogues in the biological assay. This observation was further supported by molecular modeling studies using CoMFA.

scholarly journals Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension

2018 ◽  
Vol 315 (5) ◽  
pp. H1304-H1315 ◽  
Author(s):  
Janice M. Diaz-Otero ◽  
Ting-Chieh Yen ◽  
Courtney Fisher ◽  
Daniel Bota ◽  
William F. Jackson ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Angiotensin Ii ◽  
Mineralocorticoid Receptor ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Myogenic Tone ◽  
Transient Receptor Potential Vanilloid ◽  
Cerebrovascular Function ◽  
Transient Receptor

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16−18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg−1·min−1) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg−1·day−1) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5–14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10−9–10−5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10−5 mol/l) and indomethacin (10−4 mol/l). We used GSK2193874 (10−7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10−9–10−5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension. NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.

scholarly journals The expression profile of acid-sensing ion channel (ASIC) subunits ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 in the esophageal vagal afferent nerve subtypes

2014 ◽  
Vol 307 (9) ◽  
pp. G922-G930 ◽  
Author(s):  
Svetlana Dusenkova ◽  
Fei Ru ◽  
Lenka Surdenikova ◽  
Christina Nassenstein ◽  
Jozef Hatok ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Expression Profile ◽  
Transient Receptor Potential ◽  
Splice Variants ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Nociceptive Neurons ◽  
Acid Sensitivity ◽  
Vagal Afferent ◽  
Transient Receptor

Acid-sensing ion channels (ASICs) have been implicated in esophageal acid sensing and mechanotransduction. However, insufficient knowledge of ASIC subunit expression profile in esophageal afferent nerves hampers the understanding of their role. This knowledge is essential because ASIC subunits form heteromultimeric channels with distinct functional properties. We hypothesized that the esophageal putative nociceptive C-fiber nerves (transient receptor potential vanilloid 1, TRPV1-positive) express multiple ASIC subunits and that the ASIC expression profile differs between the nodose TRPV1-positive subtype developmentally derived from placodes and the jugular TRPV1-positive subtype derived from neural crest. We performed single cell RT-PCR on the vagal afferent neurons retrogradely labeled from the esophagus. In the guinea pig, nearly all (90%–95%) nodose and jugular esophageal TRPV1-positive neurons expressed ASICs, most often in a combination (65–75%). ASIC1, ASIC2, and ASIC3 were expressed in 65–75%, 55–70%, and 70%, respectively, of both nodose and jugular TRPV1-positive neurons. The ASIC1 splice variants ASIC1a and ASIC1b and the ASIC2 splice variant ASIC2b were similarly expressed in both nodose and jugular TRPV1-positive neurons. However, ASIC2a was found exclusively in the nodose neurons. In contrast to guinea pig, ASIC3 was almost absent from the mouse vagal esophageal TRPV1-positive neurons. However, ASIC3 was similarly expressed in the nonnociceptive TRPV1-negative (tension mechanoreceptors) neurons in both species. We conclude that the majority of esophageal vagal nociceptive neurons express multiple ASIC subunits. The placode-derived nodose neurons selectively express ASIC2a, known to substantially reduce acid sensitivity of ASIC heteromultimers. ASIC3 is expressed in the guinea pig but not in the mouse vagal esophageal TRPV1-positive neurons, indicating species differences in ASIC expression.

scholarly journals Role of Gangliosides in Peripheral Pain Mechanisms

2020 ◽  
Vol 21 (3) ◽  
pp. 1005 ◽  
Author(s):  
Péter Sántha ◽  
Ildikó Dobos ◽  
Gyöngyi Kis ◽  
Gábor Jancsó
Keyword(s):  
Ion Channels ◽  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Membrane Receptors ◽  
Transient Receptor Potential Vanilloid ◽  
Pain Mechanisms ◽  
Novel Approach ◽  
Transient Receptor ◽  
Nociceptive Ion Channels

Gangliosides are abundantly occurring sialylated glycosphingolipids serving diverse functions in the nervous system. Membrane-localized gangliosides are important components of lipid microdomains (rafts) which determine the distribution of and the interaction among specific membrane proteins. Different classes of gangliosides are expressed in nociceptive primary sensory neurons involved in the transmission of nerve impulses evoked by noxious mechanical, thermal, and chemical stimuli. Gangliosides, in particular GM1, have been shown to participate in the regulation of the function of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1), a molecular integrator of noxious stimuli of distinct nature. Gangliosides may influence nociceptive functions through their association with lipid rafts participating in the organization of functional assemblies of specific nociceptive ion channels with neurotrophins, membrane receptors, and intracellular signaling pathways. Genetic and experimentally induced alterations in the expression and/or metabolism of distinct ganglioside species are involved in pathologies associated with nerve injuries, neuropathic, and inflammatory pain in both men and animals. Genetic and/or pharmacological manipulation of neuronal ganglioside expression, metabolism, and action may offer a novel approach to understanding and management of pain.

Stretch-activated cation channel TRPV4 mediates hyposmotically induced prolactin release from prolactin cells of mozambique tilapia Oreochromis mossambicus

2012 ◽  
Vol 302 (8) ◽  
pp. R1004-R1011 ◽  
Author(s):  
Soichi Watanabe ◽  
Andre P. Seale ◽  
E. Gordon Grau ◽  
Toyoji Kaneko
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Immunohistochemical Analysis ◽  
Ruthenium Red ◽  
Cation Channel ◽  
Transient Receptor Potential Vanilloid ◽  
Functional Assay ◽  
Mozambique Tilapia ◽  
Transient Receptor ◽  
Rostral Pars Distalis

In teleost fish, prolactin (PRL) is an important hormone for hyperosmoregulation. The release of PRL from the pituitary of Mozambique tilapia is stimulated by a decrease in extracellular osmolality. Previous studies have shown that hyposmotically induced PRL release is linked with cell volume changes, and that stretch-activated Ca2+ channels are likely responsible for the initiation of the signal transduction for PRL release. In this study, we identified the stretch-activated Ca2+ channel transient receptor potential vanilloid 4 (TRPV4) from the rostral pars distalis (RPD) of tilapia acclimated to freshwater (FW). TRPV4 transcripts were ubiquitously expressed in tilapia; the level of expression in RPDs of FW-acclimated fish was lower than that found in RPDs of seawater (SW)-acclimated fish. Immunohistochemical analysis of the pituitary revealed that TRPV4 is localized in the cell membrane of PRL cells of both FW and SW tilapia. A functional assay with CHO-K1 cells showed that tilapia TRPV4 responded to a decrease in extracellular osmolality, and that its function was suppressed by ruthenium red (RR) and activated by 4α-phorbol 12,13-didecanoate (4aPDD). Exposure of dissociated PRL cells from FW-acclimated tilapia to RR blocked hyposmolality induced PRL release. PRL release, on the other hand, was stimulated by 4aPDD. These results indicate that PRL release in response to physiologically relevant changes in extracellular osmolality is mediated by the osmotically sensitive TRPV4 cation channel.

scholarly journals Role of transient receptor potential vanilloid 1 in the modulation of airway smooth muscle tone and calcium handling

2017 ◽  
Vol 312 (6) ◽  
pp. L812-L821 ◽  
Author(s):  
Gene T. Yocum ◽  
Jun Chen ◽  
Christine H. Choi ◽  
Elizabeth A. Townsend ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Airway Smooth Muscle ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Nerve Fibers ◽  
Calcium Oscillations ◽  
Transient Receptor Potential Vanilloid ◽  
Organ Bath ◽  
Transient Receptor

Asthma is a common disorder characterized, in part, by airway smooth muscle (ASM) hyperresponsiveness. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel expressed on airway nerve fibers that modulates afferent signals, resulting in cough, and potentially bronchoconstriction. In the present study, the TRPV1 transcript was detected by RT-PCR in primary cultured human ASM cells, and the TRPV1 protein was detected in ASM of human trachea by immunohistochemistry. Proximity ligation assays suggest that TRPV1 is expressed in the sarcoplasmic reticulum membrane of human ASM cells in close association with sarco/endoplasmic reticulum Ca2+-ATPase-2. In guinea pig tracheal ring organ bath experiments, the TRPV1 agonist capsaicin led to ASM contraction, but this contraction was significantly attenuated by the sodium channel inhibitor bupivacaine ( n = 4, P < 0.05) and the neurokinin-2 receptor antagonist GR-159897 ( n = 4, P < 0.05), suggesting that this contraction is neutrally mediated. However, pretreatment of guinea pig and human ASM in organ bath experiments with the TRPV1 antagonist capsazepine inhibited the maintenance phase of an acetylcholine-induced contraction ( n = 4, P < 0.01 for both species). Similarly, capsazepine inhibited methacholine-induced contraction of peripheral airways in mouse precision-cut lung slice (PCLS) experiments ( n = 4–5, P < 0.05). Although capsazepine did not inhibit store-operated calcium entry in mouse ASM cells in PCLS ( n = 4–7, P = nonsignificant), it did inhibit calcium oscillations ( n = 3, P < 0.001). These studies suggest that TRPV1 is expressed on ASM, including the SR, but that ASM TRPV1 activation does not play a significant role in initiation of ASM contraction. However, capsazepine does inhibit maintenance of contraction, likely by inhibiting calcium oscillations.

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