Bitopic A₃ Adenosine Receptor Molecular Probes: Positive Allosteric Modulation and Noncanonical Activation.

ABSTRACT: 1H-Imidazo[4,5-c]quinolin-4-amines are lipid-facing, positive allosteric modulators (PAMs) of the G_i-coupled A₃ adenosine receptor (A₃AR). Elongated amino-alkyl chains anchor these bitopic PAMs secondarily to anionic phospholipids in the membrane's inner leaflet. Varied terminal functionalities and introduced reporter groups, as well as N1-alkylation on the core heterocycle, substantially enhanced human A₃AR agonist (Cl-IB-MECA) potency and efficacy in [³⁵S]GTPγS binding and revealed ago-PAM activity. Docking calculations predicted N1-benzylation to reduce undesired orthosteric site binding. Fluorophores, biotin, click moieties, chemically reactive, and photouncaging groups were included. Compound 38

SUBMITTER: Kurma SH 

PROVIDER: S-EPMC12863435 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature