Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

We have repurposed
(N)-methanocarba adenosine
derivatives (A3 adenosine receptor (AR) agonists) to enhance
radioligand binding allosterically at the human dopamine (DA) transporter
(DAT) and inhibit DA uptake. We extended the structure–activity
relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine,
and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl
5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of
two structurally dissimilar radioligands was enhanced; NET binding
of only one radioligand was enhanced; SERT radioligand binding was
minimally affected. 10 was more potent than cocaine at
inhibiting DA uptake (IC50 = 107 nM). Ribose analogues
were weaker in DAT interaction than the corresponding bicyclics. Thus,
we enhanced the neurotransmitter transporter activity of rigid nucleosides
while reducing A3AR affinity.