High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

Romeo, Giuseppe; Salerno, Loredana; Pittalà, Valeria; Modica, Maria; Siracusa, M. A.; Materia, Luisa; Buccioni, Michela; Marucci, Gabriella; Minneman, Kenneth P.

doi:10.1016/j.ejmech.2014.06.057

Cited by 9 publications

(7 citation statements)

References 32 publications

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“…The α 1D -AR subtype is present in blood vessels and regulates arterial blood pressure via vasocontraction [ 48 ]. Antagonists of the α 1D -AR are thought to be therapeutically important in cardiovascular diseases occurring due to the α 1D -AR [ 23 ]. Antagonists of the α 1 -AR subtypes are important as treatments of many kinds of diseases.…”

Section: Discussionmentioning

confidence: 99%

“…In rat parotid glands, the presence of mRNA and receptor protein for both the α 1A - and α 1B -AR subtypes, along with detectable α 1D -AR mRNA, has been confirmed [ 16 , 17 ]. α 1 -AR antagonists are widely used in the treatment of lower urinary tract symptoms (LUTS) [ 18 , 19 , 20 , 21 , 22 ] and cardiovascular diseases [ 23 ]. However, α 1 -AR antagonists cause dry mouth as a side effect [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms Underlying Activation of α1-Adrenergic Receptor-Induced Trafficking of AQP5 in Rat Parotid Acinar Cells under Isotonic or Hypotonic Conditions

Bragiel

Wang

Pieczonka

et al. 2016

IJMS

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Defective cellular trafficking of aquaporin-5 (AQP5) to the apical plasma membrane (APM) in salivary glands is associated with the loss of salivary fluid secretion. To examine mechanisms of α1-adrenoceptor (AR)-induced trafficking of AQP5, immunoconfocal microscopy and Western blot analysis were used to analyze AQP5 localization in parotid tissues stimulated with phenylephrine under different osmolality. Phenylephrine-induced trafficking of AQP5 to the APM and lateral plasma membrane (LPM) was mediated via the α1A-AR subtype, but not the α1B- and α1D-AR subtypes. Phenylephrine-induced trafficking of AQP5 was inhibited by ODQ and KT5823, inhibitors of nitric oxide (NO)-stimulated guanylcyclase (GC) and protein kinase (PK) G, respectively, indicating the involvement of the NO/ soluble (c) GC/PKG signaling pathway. Under isotonic conditions, phenylephrine-induced trafficking was inhibited by La3+, implying the participation of store-operated Ca2+ channel. Under hypotonic conditions, phenylephrine-induced trafficking of AQP5 to the APM was higher than that under isotonic conditions. Under non-stimulated conditions, hypotonicity-induced trafficking of AQP5 to the APM was inhibited by ruthenium red and La3+, suggesting the involvement of extracellular Ca2+ entry. Thus, α1A-AR activation induced the trafficking of AQP5 to the APM and LPM via the Ca2+/ cyclic guanosine monophosphate (cGMP)/PKG signaling pathway, which is associated with store-operated Ca2+ entry.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Activation of α1-Adrenergic Receptor-Induced Trafficking of AQP5 in Rat Parotid Acinar Cells under Isotonic or Hypotonic Conditions

Bragiel

Wang

Pieczonka

et al. 2016

IJMS

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“…Ring-opening reactions of cyclic acid anhydrides were also performed to synthesize alkyl carboxylate analogues. Cyclic anhydrides such as succinic anhydride and Meldrum’s acid have been commonly used in the literature to form amide bonds through ring-opening reactions. − The butyric acid analogue ( 5e ) was synthesized from intermediate 4 via nucleophilic attack on the carbonyl π system present in succinic anhydride. Subsequent (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) amide coupling of 5e converted the acid moiety to the corresponding carboxamide 5f .…”

Section: Resultsmentioning

confidence: 99%

Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

et al. 2019

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Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.

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“…Although RN5 served in a series of successive studies as template molecule for the discovery of novel a 1 -AR ligands endowed with high affinity and selectivity, [28][29][30][31][32][33][34][35] a deeper study of its pharmacological properties in in vivo models did not follow the early papers reporting affinity and activity data from in vitro assays. One of the reasons of this lies in the very low aqueous solubility of RN5.…”

Section: Introductionmentioning

confidence: 99%

An α₁-adrenergic receptor ligand repurposed as a potent antiproliferative agent for head and neck squamous cell carcinoma

et al. 2015

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High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

Cited by 9 publications

References 32 publications

Mechanisms Underlying Activation of α1-Adrenergic Receptor-Induced Trafficking of AQP5 in Rat Parotid Acinar Cells under Isotonic or Hypotonic Conditions

Mechanisms Underlying Activation of α1-Adrenergic Receptor-Induced Trafficking of AQP5 in Rat Parotid Acinar Cells under Isotonic or Hypotonic Conditions

Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

An α₁-adrenergic receptor ligand repurposed as a potent antiproliferative agent for head and neck squamous cell carcinoma

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High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

Cited by 9 publications

References 32 publications

Mechanisms Underlying Activation of α1-Adrenergic Receptor-Induced Trafficking of AQP5 in Rat Parotid Acinar Cells under Isotonic or Hypotonic Conditions

Mechanisms Underlying Activation of α1-Adrenergic Receptor-Induced Trafficking of AQP5 in Rat Parotid Acinar Cells under Isotonic or Hypotonic Conditions

Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions

An α1-adrenergic receptor ligand repurposed as a potent antiproliferative agent for head and neck squamous cell carcinoma

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Product

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An α₁-adrenergic receptor ligand repurposed as a potent antiproliferative agent for head and neck squamous cell carcinoma