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, 60 (7), 3109-3123

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

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

Dilip K Tosh et al. J Med Chem.

Abstract

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.

Figures

Figure 1
Figure 1
Drug-induced enhancement of [3H]24 binding to hDAT (PDSP) by (N)-methanocarba analogues (representative of 2 - 5 determinations): (A) 3-deaza-5′-methylamide 6; (B) 5′-ethyl ester 10 and 2-(5-bromothienylethynyl)-5′-methyl ester 11; (C) 2-(5-chlorothienylethynyl)-5′-N-(2-aminoethyl)-carboxamide 8 and its 5′-ethyl ester analogue 10; (D) 5′-n-propyl ester 14 and 5′-carboxylic acid 22. Comparison with binding inhibition by 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3 phenylpropyl)-piperazine (GBR12909, 30) is shown.
Figure 2
Figure 2
(A) Drug-induced enhancement of [3H]24 binding to hDAT (PDSP) by ribosides 27 - 29 (representative of 4 determinations) in comparison to weak enhancers (N)-methanocarba 5′-N-(2-aminoethyl)-carboxamide 8 and 5′-isopropyl ester 15. Comparison with binding inhibition by 30 is shown.
Figure 3
Figure 3
Drug-induced enhancement or inhibition of [125I]23 binding and [3H]26 binding to HEK-hDAT, HEK-hNET and HEK-hSERT cell membranes.
Scheme 1
Scheme 1
Synthesis of (N)-methanocarba 5′-esters 9-21, carboxylate 22, and extended amide 8 derivatives. Reagents and Conditions (% yields): (i) 2-Chloro or 2-bromo-5-ethynylthiophene, Pd(Ph3P)2Cl2, CuI, Et3N, DMF, rt, 82-83%; (ii) 10%TFA, MeOH, 70 °C, 90-91%; (iii) for 22: 1N NaOH, MeOH, rt, 82%; (iv) for 8: ethylenediamine, MeOH, rt, 71%; (v) for 14 - 21: ROH, DCC, DMAP, DMF, rt, 51-59%; (vi) for 9, 11: MeONa, MeOH, rt, 69%.
Scheme 2
Scheme 2
Synthesis of 5′-ester and 5′-methylamides 27-29 in the riboside series. Reagents and Conditions (% yields): (i) 2,2-dimethoxypropane, acetone, p-TSA, rt, 91%; (ii) RNH2, Et3N, MeOH, rt, 83-85%; (iii) PDC, DMF, 40 °C, 67-68%; (iv) for 41, 42: RNH2, HATU, DIPEA, DMF, rt, 68-69%; (v) for 43: MeOH, DCC, DMAP, DMF, rt, 52%; (vi) 2-chloro-5-ethynylthiophene, Pd(Ph3P)2Cl2, CuI, Et3N, DMF, rt, 82-84%; (iv) 10%TFA, MeOH, 70 °C, 90-91%.
Scheme 3
Scheme 3
Synthesis of 3-deaza-(N)-methanocarbanucleosides 6 and 13. Reagent and Conditions (% yields): (i) 3-deaza-2-bromo-6-chloropurine, Ph3P, DIAD, THF, 69%; (ii) MeNH2.HCl, DIPEA, isopropanol, 125 °C, microwave, 76%; (iii) 40% MeNH2, MeOH, rt; (iv) 5-chloro-2-ethynylthiophene, PdCl2(Ph3P)2, CuI, DMF, 130 °C, μwave, 63%; (v) 10%TFA, MeOH, 70 °C, 90-91%.
Chart 1
Chart 1
Structures of potent A3AR agonists that displayed activity at hDAT.

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