Synthesis of Terminal Ribose Analogues of Adenosine 5'-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2.
J Org Chem
; 84(10): 6143-6157, 2019 05 17.
Article
em En
| MEDLINE
| ID: mdl-30978018
ABSTRACT
TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5'-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9 H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2'-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2â³-based analogues proved to be unstable. The C1â³- and C3â³-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1â³-ß- O-methyl-2â³,3â³- O-isopropylidene derivative was evaluated. Removal of either C1â³ or C3â³ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sondas Moleculares
/
Adenosina Difosfato Ribose
/
Canais de Cátion TRPM
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article