Abstract

We have prepared a series of adenosine analogs based on the bicyclo[2.2.1]heptane scaffold of locked nucleic acid (LNA) and tested them for both agonist and antagonist activity at the adenosine A₃ receptor. The design of these derivatives was based on the known A₃ agonist IB-MECA and related compounds. Modifications thus include the 5′-uronamides and N⁶-(3-iodobenzyl) derivatives. In this way we have prepared analogs of known A₃ agonists with the sugar ring restricted in an N-conformation. For comparison we have also prepared 2′-O-methyl derivatives of IB-MECA. The LNA nucleosides showed no agonist activity but some of them are potent antagonists. The 2′-O-methyl derivative of IB-MECA is an agonist with similar potency as the parent compound.

Graphical abstract

Locked nucleic acid (LNA) analogs of the A₃AR agonist IB-MECA.

Full-size image (3K)

Keywords: LNA; Amino-LNA; Adenosine A₃ receptor; IB-MECA

Article Outline

1. Introduction

2. Results and discussion

2.1. Chemistry

2.2. Adenosine A₃ receptor activity

3. Experimental

3.1. General procedures

3.1.1. (1R,3R,4R,7S)-(7-Benzyloxy-3-(adenin-9-yl)-2,5-dioxabicyclo[2:2:1]hept-1-yl)-N-methylcarboxamide (23)

3.1.2. (1R,3R,4R,7S)-(7-Hydroxy-3-(adenin-9-yl)-2,5-dioxabicyclo[2:2:1]hept-1-yl)-N-methylcarboxamide (11)

3.1.3. (1S,3R,4R,7S)-7-Hydroxy-1-hydroxymethyl-3-(N⁶-(3-iodobenzyl)-adenin-9-yl)-2,5-dioxabicyclo[2:2:1]heptane (12)

3.1.4. (1R,3R,4R,7S)-(7-Hydroxy-3-(N⁶-(3-iodobenzyl)-adenin-9-yl)-2,5-dioxabicyclo[2:2:1]hept-1-yl)-N-methylcarboxamide (13)

3.1.5. (1R,3R,4R,7S)-7-Benzyloxy-5-tert-butoxycarbonyl-1-hydroxymethyl-3-(adenine-9-yl)-2-oxa-5-aza-bicyclo[2:2:1]heptane (25)

3.1.6. (1R,3R,4R,7S)-(7-Hydroxy-3-(adenin-9-yl)-2-oxa-5-azabicyclo[2:2:1]hept-1-yl)-N-methylcarboxamide (15)

3.1.7. (1S,3R,4R,7S)-7-Hydroxy-1-hydroxymethyl-3-(N⁶-(3-iodobenzyl)-adenin-9-yl)-2-oxa-5-azabicyclo[2:2:1]heptane (16)

3.1.8. (1R,3R,4R,7S)-7-Benzyloxy-5-tert-butoxycarbonyl-1-hydroxymethyl-3-(N⁶-(3-iodobenzyl)-adenine-9-yl)-2-oxa-5-aza-bicyclo[2:2:1]heptane (26)

3.1.9. (1R,3R,4R,7S)-(7-Hydroxy-3-(N⁶-(3-iodobenzyl)-adenin-9-yl)-2-oxa-5-azabicyclo[2:2:1]hept-1-yl)-N-methylcarboxamide (17)

3.1.10. 2′-O-Methyladenosine-N-methyl-5′-uronamide (19)

3.1.11. N⁶-(3-Iodobenzyl)-2′-O-methyladenosine (20)

3.1.12. N⁶-(3-Iodobenzyl)-2′-O-methyladenosine-N-methyl-5′-uronamide (21)

3.2. Human adenosine A₃ receptor assay

3.3. Human adenosine A₁ receptor assay

References