102704-40-5Relevant articles and documents
A practical indium tribromide catalysed addition of indoles to nitroalkenes in aqueous media
Bandini, Marco,Melchiorre, Paolo,Melloni, Alfonso,Umani-Ronchi, Achille
, p. 1110 - 1114 (2002)
The 1,4-conjugate addition of indoles to nitroalkenes was efficiently carried out in aqueous media using a catalytic amount of indium tribromide (5 mol%). The reusability of the indium tribromide was tested by performing consecutive cycles with the same c
Preparation of spiro[indole-3,5′-isoxazoles] via Grignard conjugate addition/spirocyclization sequence
Aksenov, Alexander V.,Aksenov, Dmitrii A.,Aksenov, Nicolai A.,Skomorokhov, Anton A.,Aleksandrova, Elena V.,Rubin, Michael
, p. 1783 - 1793 (2021)
A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Br?nsted acid-assisted spirocyclization allowed for preparation of 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4′-alkylsubstituted derivatives hardly available by other means.
Nitrostyrenes as 1,4-CCNO-dipoles: diastereoselective formal [4+1] cycloaddition of indoles
Aksenov, Alexander V.,Aksenov, Nicolai A.,Aksenov, Dmitrii A.,Khamraev, Vladislav F.,Rubin, Michael
, p. 13260 - 13263 (2018)
An unusual reactivity of nitrostyrenes in phosphorous acid was discovered, which permits the employment of these readily available synthons as 1,4-CCNO-dipole surrogates in a highly diastereoselective (4+1)-cycloaddition of indoles to afford 4′H-spiro[ind
Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor
Laprairie, Robert B.,Kulkarni, Pushkar M.,Deschamps, Jeffrey R.,Kelly, Melanie E. M.,Janero, David R.,Cascio, Maria G.,Stevenson, Lesley A.,Pertwee, Roger G.,Kenakin, Terrence P.,Denovan-Wright, Eileen M.,Thakur, Ganesh A.
, p. 1188 - 1203 (2017)
The cannabinoid 1 receptor (CB1R) is one of the most widely expressed metabotropic G protein-coupled receptors in brain, and its participation in various (patho)physiological processes has made CB1R activation a viable therapeutic modality. Adverse psychotropic effects limit the clinical utility of CB1R orthosteric agonists and have promoted the search for CB1R positive allosteric modulators (PAMs) with the promise of improved drug-like pharmacology and enhanced safety over typical CB1R agonists. In this study, we describe the synthesis and in vitro and ex vivo pharmacology of the novel allosteric CB1R modulator GAT211 (racemic) and its resolved enantiomers, GAT228 (R) and GAT229 (S). GAT211 engages CB1R allosteric site(s), enhances the binding of the orthosteric full agonist [3H]CP55,490, and reduces the binding of the orthosteric antagonist/inverse agonist [3H]SR141716A. GAT211 displayed both PAM and agonist activity in HEK293A and Neuro2a cells expressing human recombinant CB1R (hCB1R) and in mouse-brain membranes rich in native CB1R. GAT211 also exhibited a strong PAM effect in isolated vas deferens endogenously expressing CB1R. Each resolved and crystallized GAT211 enantiomer showed a markedly distinctive pharmacology as a CB1R allosteric modulator. In all biological systems examined, GAT211's allosteric agonist activity resided with the R-(+)-enantiomer (GAT228), whereas its PAM activity resided with the S-(-)-enantiomer (GAT229), which lacked intrinsic activity. These results constitute the first demonstration of enantiomer-selective CB1R positive allosteric modulation and set a precedent whereby enantiomeric resolution can decisively define the molecular pharmacology of a CB1R allosteric ligand.
Direct conversion of 3-(2-nitroethyl)-1H-indoles into 2-(1H-indol-2-yl)acetonitriles
Aksenov, Alexander V.,Aksenov, Dmitrii A.,Aksenov, Nicolai A.,Aleksandrova, Elena V.,Grishin, Igor Yu.,Rubin, Michael,Sorokina, Elena A.,Wenger, Allison
, (2021/10/20)
The recently discovered [4+1]-spirocyclization of nitroalkenes to indoles provided a convenient new approach to 2-(1H-indol-2-yl)acetonitriles. However, this reaction was complicated by the formation of inert 3-(2-nitroethyl)-1H-indole byproducts. Herein,
Focused structure-activity relationship profiling around the 2-phenylindole scaffold of a cannabinoid type-1 receptor agonist-positive allosteric modulator: site-III aromatic-ring congeners with enhanced activity and solubility
Schaffer, Peter C.,Kulkarni, Pushkar M.,Janero, David R.,Thakur, Ganesh A.
, (2020/09/11)
Specific tuning of cannabinoid 1 receptor (CB1R) activity by small-molecule allosteric modulators is a therapeutic modality with multiple properties inherently advantageous to therapeutic applications. We previously generated a library of unique CB1R posi
Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators
Garai, Sumanta,Kulkarni, Pushkar M.,Schaffer, Peter C.,Leo, Luciana M.,Brandt, Asher L.,Zagzoog, Ayat,Black, Tallan,Lin, Xiaoyan,Hurst, Dow P.,Janero, David R.,Abood, Mary E.,Zimmowitch, Anaelle,Straiker, Alex,Pertwee, Roger G.,Kelly, Melanie,Szczesniak, Anna-Maria,Denovan-Wright, Eileen M.,Mackie, Ken,Hohmann, Andrea G.,Reggio, Patricia H.,Laprairie, Robert B.,Thakur, Ganesh A.
, p. 542 - 568 (2020/02/04)
Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, β-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
Synthesis of Spiro[indole-3,5′-isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles
Aksenov, Alexander V.,Aksenov, Dmitrii A.,Arutiunov, Nikolai A.,Aksenov, Nicolai A.,Aleksandrova, Elena V.,Zhao, Zhenze,Du, Liqin,Kornienko, Alexander,Rubin, Michael
, p. 7123 - 7137 (2019/06/18)
An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.
Design of a Primary-Amide-Functionalized Highly Efficient and Recyclable Hydrogen-Bond-Donating Heterogeneous Catalyst for the Friedel-Crafts Alkylation of Indoles with β-Nitrostyrenes
Markad, Datta,Mandal, Sanjay K.
, p. 3165 - 3173 (2019/03/26)
A primary-amide-functionalized metal organic framework, {[Zn2(2-BQBG)(BDC)2]·10H2O}n (1) (in which 2-BQBG = 2,2′-(butane-1,4-diylbis((quinolin-2-ylmethyl)azanediyl))diacetamide and BDC = 1,4-benzenedicarboxylate
Friedel-Crafts alkylation reaction with fluorinated alcohols as hydrogen-bond donors and solvents
Tang, Ren-Jin,Milcent, Thierry,Crousse, Benoit
, p. 10314 - 10317 (2018/03/26)
An effective and clean FC alkylation of indoles and electron-rich arenes with β-nitroalkenes in HFIP was reported. The desired products are formed rapidly in excellent yields under mild conditions without the need for any additional catalysts or reagents. Further, this methodology can be applied to one-pot synthesis of biologically active tryptamine derivatives.
