NDLI: Structure-Based Design, Synthesis by Click Chemistry and in Vivo Activity of Highly Selective A3 Adenosine Receptor Agonists

Please wait, while we are loading the content...

Year: 2016, Volume: 7

Year: 2015, Volume: 6

Year: 2015, Volume: 6, Issue: Unspecified

Structure-Based Design, Synthesis by Click Chemistry and in Vivo Activity of Highly Selective A3 Adenosine Receptor Agonists

Discovery, synthesis and structure-activity analysis of symmetrical 2,7-disubstituted fluorenones as urea transporter inhibitors

Year: 2015, Volume: 6, Issue: 10

Year: 2015, Volume: 6, Issue: 8

Year: 2015, Volume: 6, Issue: 6

Year: 2015, Volume: 6, Issue: 5

Year: 2015, Volume: 6, Issue: 4

Year: 2015, Volume: 6, Issue: 3

Year: 2015, Volume: 6, Issue: 2

Year: 2015, Volume: 6, Issue: 1

Year: 2014, Volume: 5

Year: 2013, Volume: 2013

Year: 2013, Volume: 4

Year: 2012, Volume: Unspecified

Year: 2012, Volume: 3

Year: 2011, Volume: 2

Year: 2010, Volume: 1

Structure-Based Design, Synthesis by Click Chemistry and in Vivo Activity of Highly Selective A3 Adenosine Receptor Agonists

Content Provider	PubMed Central
Author	Tosh, Dilip K. Paoletta, Silvia Chen, Zhoumou Crane, Steven Lloyd, John Gao, Zhan-guo Gizewski, Elizabeth T. Auchampach, John A. Salvemini, Daniela Jacobson, Kenneth A.
Abstract	2-Arylethynyl derivatives of (N)-methanocarba adenosine 5′-uronamides are selective A3AR (adenosine receptor) agonists. Here we substitute a 1,2,3-triazol-1-yl linker in place of the rigid, linear ethynyl group to eliminate its potential metabolic liability. Docking of nucleosides containing possible short linker moieties at the adenine C2 position using a hybrid molecular model of the A3AR (based on the A2AAR agonist-bound structure) correctly predicted that a triazole would maintain the A3AR selectivity, due to its ability to fit a narrow cleft in the receptor. The analogues with various N 6 and C2-aryltriazolyl substitution were synthesized and characterized in binding (Ki at hA3AR 0.3 – 12 nM) and in vivo to demonstrate efficacy in controlling chronic neuropathic pain (chronic constriction injury). Among N 6-methyl derivatives, a terminal pyrimidin-2-yl group in 9 (MRS7116) increased duration of action (36% pain protection at 3 h) in vivo. N 6-Ethyl 5-chlorothien-2-yl analogue 15 (MRS7126) preserved in vivo efficacy (85% protection at 1 h) with short duration. Larger N 6 groups, e.g. 17 (MRS7138, >90% protection at 1 and 3 h), greatly enhanced in vivo activity. Thus, we have combined structure-based methods and phenotypic screening to identify nucleoside derivatives having translational potential.
Related Links	http://dx.doi.org/10.1039/c4md00571f
Ending Page	563
Page Count	9
Starting Page	555
File Format	PDF
ISSN	20402503
e-ISSN	20402511
Journal	MedChemComm
Volume Number	6
Language	English
Publisher Date	2015-01-01
Access Restriction	Open
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Drug Discovery Biochemistry Pharmacology Molecular Medicine Pharmaceutical Science

Central Library (ISO-9001:2015 Certified)
Indian Institute of Technology Kharagpur
Kharagpur, West Bengal, India | PIN - 721302

See location in the Map
03222 282435
Mail: support@ndl.gov.in

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in