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. 2014 Jan 15;87(2):321-31.
doi: 10.1016/j.bcp.2013.10.011. Epub 2013 Oct 23.

Different efficacy of adenosine and NECA derivatives at the human A3 adenosine receptor: insight into the receptor activation switch

Diego Dal Ben  1 , Michela Buccioni  1 , Catia Lambertucci  1 , Sonja Kachler  2 , Nico Falgner  2 , Gabriella Marucci  1 , Ajiroghene Thomas  1 , Gloria Cristalli  1 , Rosaria Volpini  1 , Karl-Norbert Klotz  3
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Different efficacy of adenosine and NECA derivatives at the human A3 adenosine receptor: insight into the receptor activation switch

Diego Dal Ben et al. Biochem Pharmacol. .

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.

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.

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