No abstract

Running Title: Investigating adenosine receptor selectivity of N 6 -modified agonists.Keywords: GPCRs; adenosine receptor; selectivity; G proteins; yeast. 2 AbstractA series of N 6 -bicyclic and N 6 -(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N 6 -adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes these compounds might have therapeutic potential.3

Seeing things as they really are: The enzyme catalyzing the central cleavage of β‐carotene (1) to retinal (2) is not, as previously thought, a dioxygenase. Incubation of the substrate analogue α‐carotene in the presence of highly enriched 17O2 and H218O revealed a monooxygenase mechanism.

Two Ru‐porphyrin‐linked β‐cyclodextrin units form the supramolecular system, which as an enzyme mimic for β,β‐carotene 15,15′‐dioxgenase binds two substrates of the enzyme with Ka>106 M−1 and selectively catalyzes the cleavage of the central carotinoid bond in the presence of tert‐butylhydroperoxide (see picture). Mechanistic aspects of this unusual cleavage of E‐configured, conjugated double bonds are discussed.

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.