title: Different efficacy of adenosine and NECA derivatives at the human A3 adenosine receptor: insight into the receptor activation switch.
abstract: A3 Adenosine receptors are promising drug targets for a number of diseases and intense efforts are dedicated to develop selective agonists and antagonists of these receptors. A series of adenosine derivatives with 2-(ar)-alkynyl chains, with high affinity and different degrees of selectivity for human A3 adenosine receptors was tested for the ability to inhibit forskolin-stimulated adenylyl cyclase. All these derivatives are partial agonists at A3 adenosine receptors; their efficacy is not significantly modified by the introduction of small alkyl substituents in the N(6)-position. In contrast, the adenosine-5'-N-ethyluronamide (NECA) analogs of 2-(ar)-alkynyladenosine derivatives are full A3 agonists. Molecular modeling analyses were performed considering both the conformational behavior of the ligands and the impact of 2- and 5'-substituents on ligand-target interaction. The results suggest an explanation for the different agonistic behavior of adenosine and NECA derivatives, respectively. A sub-pocket of the binding site was analyzed as a crucial interaction domain for receptor activation.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, I-62032 Camerino, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, I-62032 Camerino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, I-62032 Camerino, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.affiliation: Universität Würzburg, Institut für Pharmakologie und Toxikologie, Versbacher Str. 9, D-97078, Würzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.affiliation: Universität Würzburg, Institut für Pharmakologie und Toxikologie, Versbacher Str. 9, D-97078, Würzburg, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Falgner
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, I-62032 Camerino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, I-62032 Camerino, Italy.
authors.forename: Ajiroghene
authors.initials: A
authors.lastname: Thomas
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, I-62032 Camerino, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, I-62032 Camerino, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.affiliation: Universität Würzburg, Institut für Pharmakologie und Toxikologie, Versbacher Str. 9, D-97078, Würzburg, Germany. Electronic address: klotz@toxi.uni-wuerzburg.de.
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D017433:Protein Structure, Secondary / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D043684:Receptor, Adenosine A3; D019830:Adenosine-5'-(N-ethylcarboxamide); D000241:Adenosine
keywords: 2-(3-hydroxy-3-phenyl)propyn-1-yl-N(6)-methyladenosine; 2-(3-hydroxy-3-phenyl)propyn-1-yl-adenosine; 2-(3-hydroxy-3-phenyl)propyn-1-yl-adenosine-5′-N-ethyluronamide; 2-chloro-N(6)-cyclopentyladenosine; 2-hexyn-1-yl-N(6)-methyladenosine; 2-hexyn-1-yl-adenosine; 2-hexyn-1-yl-adenosine-5′-N-ethyluronamide; 2-phenylethynyladenosine; 2-phenylethynyladenosine-5′-N-ethyluronamide; A(3); AR; Adenosine (PubChem CID: 60961); Adenosine receptor; Ado; Agonist; CCPA; CPA; EL; Efficacy; G protein-coupled receptor; GPCR; HEADO; HEMADO; HENECA; HENECA (PubChem CID: 164437); MECA; Molecular modeling; N(6)-cyclopentyladenosine; N(6)-methyl-2-phenylethynyladenosine; NECA; NECA (PubChem CID: 448222); PEADO; PEMADO; PENECA; PHPADO; PHPMADO; PHPNECA; PHPNECA (PubChem CID: 44339675); TM; adenosine; adenosine receptor; adenosine-5′-N-ethyluronamide; adenosine-5′-N-methyluronamide; extracellular; nanosecond; ns; picosecond; ps; transmembrane