Molecular probes for the A₂A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold
Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A₂A adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The co...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (9), p.2740-2745 |
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| creator | Kumar, T. Santhosh Mishra, Shilpi Deflorian, Francesca Yoo, Lena S Phan, Khai Kecskés, Miklos Szabo, Angela Shinkre, Bidhan Gao, Zhan-Guo Trenkle, William Jacobson, Kenneth A |
| description | Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A₂A adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for ¹⁸F incorporation), and fluorophore reporter groups (e.g., BODIPY conjugate 14, Kᵢ 15nM). The potent and A₂AAR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A₂AAR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A₂AAR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A₂AAR. |
| doi_str_mv | 10.1016/j.bmcl.2010.11.082 |
| format | Article |
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Santhosh ; Mishra, Shilpi ; Deflorian, Francesca ; Yoo, Lena S ; Phan, Khai ; Kecskés, Miklos ; Szabo, Angela ; Shinkre, Bidhan ; Gao, Zhan-Guo ; Trenkle, William ; Jacobson, Kenneth A</creator><creatorcontrib>Kumar, T. Santhosh ; Mishra, Shilpi ; Deflorian, Francesca ; Yoo, Lena S ; Phan, Khai ; Kecskés, Miklos ; Szabo, Angela ; Shinkre, Bidhan ; Gao, Zhan-Guo ; Trenkle, William ; Jacobson, Kenneth A</creatorcontrib><description>Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A₂A adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for ¹⁸F incorporation), and fluorophore reporter groups (e.g., BODIPY conjugate 14, Kᵢ 15nM). The potent and A₂AAR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A₂AAR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A₂AAR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A₂AAR.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.11.082</identifier><identifier>PMID: 21185184</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Adenosine A2 Receptor Antagonists ; amines ; antagonists ; Biological and medical sciences ; condensation ; Drug Design ; Humans ; Medical sciences ; Models, Molecular ; Molecular Probes - chemical synthesis ; Molecular Probes - chemistry ; Molecular Structure ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. 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Santhosh</creatorcontrib><creatorcontrib>Mishra, Shilpi</creatorcontrib><creatorcontrib>Deflorian, Francesca</creatorcontrib><creatorcontrib>Yoo, Lena S</creatorcontrib><creatorcontrib>Phan, Khai</creatorcontrib><creatorcontrib>Kecskés, Miklos</creatorcontrib><creatorcontrib>Szabo, Angela</creatorcontrib><creatorcontrib>Shinkre, Bidhan</creatorcontrib><creatorcontrib>Gao, Zhan-Guo</creatorcontrib><creatorcontrib>Trenkle, William</creatorcontrib><creatorcontrib>Jacobson, Kenneth A</creatorcontrib><title>Molecular probes for the A₂A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A₂A adenosine receptor (AR). 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In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A₂AAR.</description><subject>Adenosine A2 Receptor Antagonists</subject><subject>amines</subject><subject>antagonists</subject><subject>Biological and medical sciences</subject><subject>condensation</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Probes - chemical synthesis</subject><subject>Molecular Probes - chemistry</subject><subject>Molecular Structure</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>X-radiation</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc9u1DAQxi0EotvCC3AAX7htlhnbcZIL0qrin1TEASohVSvLccZtVtk4srdIRZz6qH0SHG0pcBpp5vd9M5qPsRcIKwTUb7ardueGlYC5gSuoxSO2QKVVIRWUj9kCGg1F3ajvR-w4pS0AKlDqKTsSiHWJtVqwX5_DQO56sJFPMbSUuA-R76-Ir-9ub9fcdjSG1I_EIzma9nnY2kQdDyO3fLqJ9mcYwoVayoI2F7gUS7XZx_7QxWVZuE2G-l3f9WNRFnY3WyVnvQ9D94w98XZI9Py-nrDz9---nX4szr58-HS6PiucrEAU1DVeaHIO6kprAQTKE9SEmnRbaeUVOCeV0OhE662ypOoOPHStcJ5kJ0_Y24PvdN3uqHM07qMdzJTvsvHGBNub_ydjf2Uuww8jocYGMBuIg4GLIaVI_kGLYOYszNbMWZg5C4NochZZ9PLfrQ-SP8_PwOt7wOaPDD7a0fXpL6ewVLJqMvfqwHkbjL2MmTn_mjeVOVCpKlHL3_uin0M</recordid><startdate>20110501</startdate><enddate>20110501</enddate><creator>Kumar, T. Santhosh</creator><creator>Mishra, Shilpi</creator><creator>Deflorian, Francesca</creator><creator>Yoo, Lena S</creator><creator>Phan, Khai</creator><creator>Kecskés, Miklos</creator><creator>Szabo, Angela</creator><creator>Shinkre, Bidhan</creator><creator>Gao, Zhan-Guo</creator><creator>Trenkle, William</creator><creator>Jacobson, Kenneth A</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20110501</creationdate><title>Molecular probes for the A₂A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold</title><author>Kumar, T. Santhosh ; Mishra, Shilpi ; Deflorian, Francesca ; Yoo, Lena S ; Phan, Khai ; Kecskés, Miklos ; Szabo, Angela ; Shinkre, Bidhan ; Gao, Zhan-Guo ; Trenkle, William ; Jacobson, Kenneth A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3702-ed9f26ecc0876620e04fe08e16e6b764f40cc34261c2bfa4ae48d0f0db2cfe3d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adenosine A2 Receptor Antagonists</topic><topic>amines</topic><topic>antagonists</topic><topic>Biological and medical sciences</topic><topic>condensation</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Probes - chemical synthesis</topic><topic>Molecular Probes - chemistry</topic><topic>Molecular Structure</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>X-radiation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumar, T. Santhosh</creatorcontrib><creatorcontrib>Mishra, Shilpi</creatorcontrib><creatorcontrib>Deflorian, Francesca</creatorcontrib><creatorcontrib>Yoo, Lena S</creatorcontrib><creatorcontrib>Phan, Khai</creatorcontrib><creatorcontrib>Kecskés, Miklos</creatorcontrib><creatorcontrib>Szabo, Angela</creatorcontrib><creatorcontrib>Shinkre, Bidhan</creatorcontrib><creatorcontrib>Gao, Zhan-Guo</creatorcontrib><creatorcontrib>Trenkle, William</creatorcontrib><creatorcontrib>Jacobson, Kenneth A</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumar, T. Santhosh</au><au>Mishra, Shilpi</au><au>Deflorian, Francesca</au><au>Yoo, Lena S</au><au>Phan, Khai</au><au>Kecskés, Miklos</au><au>Szabo, Angela</au><au>Shinkre, Bidhan</au><au>Gao, Zhan-Guo</au><au>Trenkle, William</au><au>Jacobson, Kenneth A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular probes for the A₂A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>21</volume><issue>9</issue><spage>2740</spage><epage>2745</epage><pages>2740-2745</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A₂A adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for ¹⁸F incorporation), and fluorophore reporter groups (e.g., BODIPY conjugate 14, Kᵢ 15nM). The potent and A₂AAR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A₂AAR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A₂AAR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A₂AAR.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21185184</pmid><doi>10.1016/j.bmcl.2010.11.082</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2011-05, Vol.21 (9), p.2740-2745 |
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| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adenosine A2 Receptor Antagonists amines antagonists Biological and medical sciences condensation Drug Design Humans Medical sciences Models, Molecular Molecular Probes - chemical synthesis Molecular Probes - chemistry Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology X-radiation |
| title | Molecular probes for the A₂A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold |
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