Synthesis and biological evaluation of purine and pyrimidine based ligands for the A3 and P2Y2 purinergic receptors

P1-receptors, or adenosine receptors, and P2Y receptors, are G-protein-coupled receptors, belonging to the purinergic receptor family. Adenosine is the natural ligand of the P1 receptors, while P2Y receptors are activated by nucleotide ligands (ATP,ADP, UTP and UDP). The adenosine receptors (P1) consist of 4 receptor subtypes: A1, A2A, A2B and A3. The P2Y receptors are subdivided in 8 subtypes: P2Y1, P2Y2,P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, P2Y14. In the first part of this work (chapter 2 and 3), we present the synthesis and biological evalutation of two series of adenosine A3 receptor ligands. In the second part (chapter 4), we discuss the synthesis and biological evaluation of new P2Y2 receptor ligands. Adenosine receptors are not only the major targets of caffeine, the most commonly consumed drug in the world, they could also be promising therapeutic targets in a wide range of conditions, including cardiovascular, inflammatory and neurodegenerative diseases. As a consequence of their numerous therapeutic possibilities and the ubiquity of the ARs, synthetic ligands need high selectivity with respect to receptor subtype and tissue to be of therapeutic value. The main approach for the discovery of selective A3AR ligands, has been the modification of the natural, non-selective ligand adenosine. Previous investigations showed that introduction of a 3’-amino group improved the selectivity for the human A3AR, while enhancing the water solubility. By introducing extra modifications, we evaluated the possibility of overcoming the A3AR affinity drop caused by this 3’-modification. We synthesized a series of hypermodified adenosine derivatives (chapter 2) and demonstrated that introduction of a 2-phenylethynyl substituent in concert with a N6-methyl group restored the A3AR receptor affinity. Based on the good results obtained with the 2-phenylethynyl modification, both on A3AR receptor selectivity and affinity, we decided to further explore the modifications at the 2-position. Therefore, we synthesized a series of 4-substituted 2-(1,2,3)-triazol- 1-yl N6-methyl adenosine analogues via Huisgen [3+2]cycloaddition (chapter 3). Combined with an unmodified ribose moiety, such 2-(1,2,3-triazol-1-yl) substitution resulted in very potent and selective A3AR antagonists, for example 2-(4- cyclopentylmethyl-1,2,3-triazol-1-yl)-N6-methyl-9-(-D-ribofuranosyl)adenine (3.10, Ki (A3AR) = 1.3 nM). The reduced efficacy resulting from such modifications at the 2-position were restored by the 4’-ethylcarbamoyl ribose modification, resulting in a series of potent an selective A3AR agonists, with 9-(5-ethylcarbamoyl--Dribofuranosyl)- N6-methyl-2-(4-pyridin-2-yl-1,2,3-triazol-1-yl) adenine as the most potent one (3.17b, Ki (A3AR) = 1.8nM). P2Y2 agonists are promising potential therapeutics for cystic fibrosis, cancer and dry eye syndrome. P2Y2 antagonists exhibit anti-inflammatory and neuroprotective effects and have been suggested as potential treatment for coronary vasospastic disorders. As for the A3AR receptor ligands, the natural, non-selective ligand uridine 5’-triphosphate was modified to gain access to more selective P2Y2 receptor ligands. Previous investigation demonstrated that the 2-thiouracil modification and the 2’-amino-2’-deoxy modification enhanced both P2Y2 receptor affinity and selectivity. Therefore, we combined these modifications, which resulted in the very potent and selective P2Y2 receptor agonist 2’-amino-2’-deoxy-2-thiouridine 5’-triphosphate (4.2, EC50 (P2Y2) = 8 nM) (chapter 4). UTP and its diverse synthesized analogues are sensitive to enzymatic degradation. Replacement of the -phosphate group by an isosteric phosphonomethyl group should enhance the metabolic stability. However, the resulting uridine 5’- phosphonodiphosphate (4.7) suffered from complete chemical hydrolysis to the corresponding 5’-phosphonate (4.50) in the buffer storage solution (chapter 4). In summary, in this thesis we succeeded to identify new selective ligands for both envisaged receptor subtypes: the A3A and the P2Y2 receptors.

Grantor dc:publisher

Ghent University. Faculty of Pharmaceutical Sciences

Year dc:date

2008

Author dc:creator

• Cosyn, Liesbet

Contributors dc:contributor

• Van Calenbergh, Serge

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://biblio.ugent.be/publication/469878
https://biblio.ugent.be/publication/469878/file/1881439

OAI identifier oai:identifier

oai:archive.ugent.be:469878