Structure-activity relationships of pyrimidine nucleotides containing a 5'-α,β-methylene diphosphonate at the P2Y6 receptor

Paola Oliva; Mirko Scortichini; Clemens Dobelmann; Shanu Jain; Varun Gopinatth; Kiran S Toti; Ngan B Phung; Anna Junker; Kenneth A Jacobson

doi:10.1016/j.bmcl.2021.128137

Structure-activity relationships of pyrimidine nucleotides containing a 5'-α,β-methylene diphosphonate at the P2Y₆ receptor

Bioorg Med Chem Lett. 2021 Aug 1:45:128137. doi: 10.1016/j.bmcl.2021.128137. Epub 2021 May 26.

Authors

Paola Oliva¹, Mirko Scortichini¹, Clemens Dobelmann², Shanu Jain¹, Varun Gopinatth¹, Kiran S Toti¹, Ngan B Phung¹, Anna Junker², Kenneth A Jacobson³

Affiliations

¹ Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
² University of Münster, European Institute for Molecular Imaging (EIMI), Waldeyerstraße 15, D-48149 Münster, Germany.
³ Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: kennethj@niddk.nih.gov.

Abstract

The G_q-coupled P2Y₆ receptor (P2Y₆R) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2Y₆R agonist and P2Y₁₄R partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2Y₆R agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2Y₆R potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2Y₁₄R, respectively. However, 3-alkyl (31-33, 37, 38), β-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2Y₆R activation. Thus, we have identified new α,β-methylene bridged N⁴-extended CDP analogues as P2Y₆R agonists that are highly selective over the P2Y₁₄R.

Keywords: Calcium mobilization; G protein-coupled receptor; P2Y(6) receptor; Pyrimidine nucleotides; Structure-activity relationship.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Diphosphonates / chemistry
Diphosphonates / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Pyrimidine Nucleotides / chemical synthesis
Pyrimidine Nucleotides / chemistry
Pyrimidine Nucleotides / pharmacology*
Receptors, Purinergic P2 / metabolism*
Structure-Activity Relationship

Substances

Diphosphonates
Pyrimidine Nucleotides
Receptors, Purinergic P2
purinoceptor P2Y6
methylene diphosphonate

Grants and funding

ZIA DK031116/ImNIH/Intramural NIH HHS/United States