Fluorescent probes for adenosine receptors: Synthesis and biology of N6-dansylaminoalkyl-substituted neca derivatives

Lighting up G protein-coupled purinergic receptors with engineered fluorescent ligands

“…Nearly ten years later, a series of fluorescent derivatives of the widely used non-selective and potent adenosine receptor agonist 5′- N -ethylcarboxamidoadenosine (NECA) were synthesized by the insertion of dansylaminoalkyl moieties (Fig. 1) to the N 6 -position of NECA with a linear alkyl spacer of increasing length (from 3 to 12 carbons) (Table 2) (Macchia et al, 1998). Interestingly, a compound of this series with a 6-carbon spacer chain ( 5 ) allowed visualizing A 1 R at the level of the rat molecular layer of the rat cerebellar cortex by means of fluorescence microscopy (Macchia et al, 1998).…”

“…1) to the N 6 -position of NECA with a linear alkyl spacer of increasing length (from 3 to 12 carbons) (Table 2) (Macchia et al, 1998). Interestingly, a compound of this series with a 6-carbon spacer chain ( 5 ) allowed visualizing A 1 R at the level of the rat molecular layer of the rat cerebellar cortex by means of fluorescence microscopy (Macchia et al, 1998). Subsequently, with the aim of overcoming difficulties related to the short excitation wavelength of certain fluorophores (i.e.…”

Synthesis of novel (benzimidazolyl)isoquinolinols and evaluation as adenosine A1 receptor tools

“…3 Fluorescent ligands have been developed for ARs, 4 including some with high AR subtype selectivity for A 3 AR. 5 There is one report of uorescent dansyl-linked N 6 NECA derivatives with subtype selectivity for rat A 1 AR, 6 however the short excitation wavelength of the dansyl uorophore is not ideal for many applications. When the same research group conjugated the lead pharmacophore-linker to longer excitation wavelength uorophores A 3 AR selective probes ensued.…”

“…When the same research group conjugated the lead pharmacophore-linker to longer excitation wavelength uorophores A 3 AR selective probes ensued. 6 Therefore there remains a need to develop uorescent ligands with high subtype selectivity for A 1 AR. One approach to the design of a uorescent ligand is to identify an existing pharmacophore with the requisite selectivity and affinity for the target receptor, and then identify a location that a linker and uorophore can be attached.…”

“…High temperature NMR spectra in DMSO-d 6 , carried out to study rotamers of 13 revealed cleavage of Fmoc, and indeed there is precedent in the literature that Fmoc cleavage can be conducted in neat DMSO at high temperature. 40 Thus, Fmoc cleavage of 13 in DMSO, followed by DDQ and air mediated aromatisation afforded 14 in comparable yield to 7 and 11.…”