Bioisosteric phentolamine analogs as potent α-adrenergic antagonists

Hong, Seoung‐Soo; Bavadekar, Supriya A.; S, Lee; Patil, Popat N.; Lalchandani, Shilpa G.; Feller, Dennis R.; Miller, Duane D.

doi:10.1016/j.bmcl.2005.07.083

Cited by 29 publications

(14 citation statements)

References 13 publications

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“…The variability of estimates of B max and K D therefore may be attributed by differences in the methods of blocking neccesary to determine non-specific binding. Brown and colleagues used 10 μ M phentolamine that is known to antagonize α 1 and α 2 adrenoceptors with higher selectivity to α 1 adrenoceptor 46 . Thus, due to the affinity to α 1 and α 2 adrenoceptor, use of phentolamine may underestimate values of B max and overestimate values of K D , as α 1 and some α 2 adrenergic sites both may be blocked.…”

Section: Discussionmentioning

confidence: 99%

Radioligand binding analysis of α2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

Phan

Landau

Jakobsen

et al. 2017

Sci Rep

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We describe a novel method of kinetic analysis of radioligand binding to neuroreceptors in brain in vivo, here applied to noradrenaline receptors in rat brain. The method uses positron emission tomography (PET) of [11C]yohimbine binding in brain to quantify the density and affinity of α2 adrenoceptors under condition of changing radioligand binding to plasma proteins. We obtained dynamic PET recordings from brain of Spraque Dawley rats at baseline, followed by pharmacological challenge with unlabeled yohimbine (0.3 mg/kg). The challenge with unlabeled ligand failed to diminish radioligand accumulation in brain tissue, due to the blocking of radioligand binding to plasma proteins that elevated the free fractions of the radioligand in plasma. We devised a method that graphically resolved the masking of unlabeled ligand binding by the increase of radioligand free fractions in plasma. The Extended Inhibition Plot introduced here yielded an estimate of the volume of distribution of non-displaceable ligand in brain tissue that increased with the increase of the free fraction of the radioligand in plasma. The resulting binding potentials of the radioligand declined by 50–60% in the presence of unlabeled ligand. The kinetic unmasking of inhibited binding reflected in the increase of the reference volume of distribution yielded estimates of receptor saturation consistent with the binding of unlabeled ligand.

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Section: Discussionmentioning

confidence: 99%

Radioligand binding analysis of α2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

Phan

Landau

Jakobsen

et al. 2017

Sci Rep

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“…Phentolamine inhibited phenylephrine DMR responses with affinity constant (pA 2 ) 5 26.93, or 117 nM ( Fig. 2E; Table 2), which is within the range of previously reported values for binding the a 1B -AR subtype (Morrow and Creese, 1986;Hong et al, 2005;Bavadekar et al, 2008). We next assayed the affinity of the quinazoline a 1 -AR-selective antagonists doxazosin (Fig.…”

Section: Resultsmentioning

confidence: 64%

Label-Free Dynamic Mass Redistribution Reveals Low-Density, Prosurvival α_1B-Adrenergic Receptors in Human SW480 Colon Carcinoma Cells

Harris

Park

Lee

et al. 2017

J Pharmacol Exp Ther

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Small molecules that target the adrenergic family of G protein-coupled receptors (GPCRs) show promising therapeutic efficacy for the treatment of various cancers. In this study, we report that human colon cancer cell line SW480 expresses low-density functional a 1B -adrenergic receptors (ARs) as revealed by label-free dynamic mass redistribution (DMR) signaling technology and confirmed by quantitative reverse-transcriptase polymerase chain reaction analysis. Remarkably, although endogenous a 1B -ARs are not detectable via either [3 H]-prazosin-binding analysis or phosphoinositol hydrolysis assays, their activation leads to robust DMR and enhanced cell viability. We provide pharmacological evidence that stimulation of a 1B -ARs enhances SW480 cell viability without affecting proliferation, whereas stimulating b-ARs diminishes both viability and proliferation of SW480 cells. Our study illustrates the power of label-free DMR technology for identifying and characterizing low-density GPCRs in cells and suggests that drugs targeting both a 1B -and b-ARs may represent valuable smallmolecule therapeutics for the treatment of colon cancer.

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“…In addition to these limitations, 1,1-diarylamines often cannot be transformed to hydrazines by this method due to the cleavage of the weak N-NO 2 bonds in the product under reducing conditions. 5 One method for circumventing these obstacles is to use copper [6][7][8] or patented palladium complexes for the amination of diarylamines; 9 however, the ligand selection process to obtain useful results is often cumbersome and somewhat unpredictable.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of reduction-sensitive 1,1-diarylhydrazines from 1,1-diarylamines

et al. 2014

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1-(2-Nitrophenyl)-1-phenylamine and methyl 4-((2-nitrophenyl)amino)benzoate have been transformed into their corresponding urea derivatives through the action of chlorosulfonyl isocyanate. The initial sulfimidate product from the former reaction has sufficient stability so that it can be isolated and characterized as its disodium salt, and this, as well as three other subsequent products, have been characterized by X-ray diffraction. The corresponding intermediary urea was converted into its hydrazine derivative via a Hofmann rearrangement under oxidative conditions. Density functional theory has been used to examine the nature of the intermediates and transition states for the Hofmann rearrangement. There is little theoretical indication for a cyclic aziridinonium intermediate and the transition state between the urea and the isocyanate corresponds to a reactant-like rotation of the planar singlet nitrene before migration and formation of the new N−N bond.Résumé : La 1-(2-nitrophényle)-1-phénylamine et la 4-((2-nitrophényle)amino)benzoate de méthyle ont été transformé par leur réaction avec l'isocyanate de chlorosulfonyle en leurs urées correspondantes. Dans le premier cas, le produit initial de cette réaction, un sulfimidé, démontre une stabilité qui permet son isolement comme sel de sodium. Celui-ci ainsi que trois produits ultérieurs ont été caractérisés par diffraction de rayons X. L'urée de 1-(2-nitrophényle)-1-phénylamine a été transformé en hydrazine par réarrangement de Hofmann sous conditions oxydatives. La théorie de la fonctionnelle de la densité a été utilisé afin d'examiner les intermédiaires et les états de transition de ce réarrangement. Les calculs indiquent qu'un intermédiaire aziridononium cyclique est peu probable et que l'état de transition qui mène de l'urée à l'isocyanate et finalement à l'hydrazine correspond à une rotation de la nitrène planaire de forme singulet avant sa migration et la formation d'une nouvelle liaison entre les deux atomes d'azote.

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Bioisosteric phentolamine analogs as potent α-adrenergic antagonists

Cited by 29 publications

References 13 publications

Radioligand binding analysis of α2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

Radioligand binding analysis of α2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

Label-Free Dynamic Mass Redistribution Reveals Low-Density, Prosurvival α_1B-Adrenergic Receptors in Human SW480 Colon Carcinoma Cells

Synthesis of reduction-sensitive 1,1-diarylhydrazines from 1,1-diarylamines

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Bioisosteric phentolamine analogs as potent α-adrenergic antagonists

Cited by 29 publications

References 13 publications

Radioligand binding analysis of α2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

Radioligand binding analysis of α2 adrenoceptors with [11C]yohimbine in brain in vivo: Extended Inhibition Plot correction for plasma protein binding

Label-Free Dynamic Mass Redistribution Reveals Low-Density, Prosurvival α1B-Adrenergic Receptors in Human SW480 Colon Carcinoma Cells

Synthesis of reduction-sensitive 1,1-diarylhydrazines from 1,1-diarylamines

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Label-Free Dynamic Mass Redistribution Reveals Low-Density, Prosurvival α_1B-Adrenergic Receptors in Human SW480 Colon Carcinoma Cells