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. 2012 Sep 27;55(18):8075-90.
doi: 10.1021/jm300965a. Epub 2012 Sep 10.

Structural sweet spot for A1 adenosine receptor activation by truncated (N)-methanocarba nucleosides: receptor docking and potent anticonvulsant activity

Dilip K Tosh  1 , Silvia Paoletta, Francesca Deflorian, Khai Phan, Steven M Moss, Zhan-Guo Gao, Xiaohui Jiang, Kenneth A Jacobson
Affiliations

Structural sweet spot for A1 adenosine receptor activation by truncated (N)-methanocarba nucleosides: receptor docking and potent anticonvulsant activity

Dilip K Tosh et al. J Med Chem. .

Abstract

A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N(6)-cycloalkylmethyl 4'-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N(6)-dicyclopropylmethyl, K(i) = 47.9 nM) as a moderately A(1)AR-selective full agonist. Two stereochemically defined N(6)-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A(1)AR selectivity. Nucleoside docking to A(1)AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger "A" forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket "B" forming contacts between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A(1)AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A(1)AR agonists. Thus, we identified highly restricted regions for substitution around N(6) suitable for an A(1)AR agonist with anticonvulsant activity.

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Figures

Figure 1
Figure 1
Graphical comparison of the most potent truncated adenosine derivatives arranged by rank order of hA1AR binding affinity (ranging from 48 nM to 270 nM). The lower plots represent the hA1AR selectivity in comparison to the hA3AR and maximal efficacy at the hA1AR (data in Table 1).
Figure 2
Figure 2
(A) Side view and (B) top view of the docking pose of compound 10 (in magenta) inside the binding site of the hA1AR model. Side chains of some amino acids important for ligand recognition and H-bonding interactions are highlighted. Hydrogen atoms are not displayed. The Connolly surface of some amino acids surrounding the binding site is displayed. Surface color indicates hydrophobic regions (green), mildly polar regions (blue) and H-bonding regions (magenta). The boundaries of the two identified subpockets are highlighted (larger subpocket A in yellow and smaller subpocket B in orange). R2 (Table 1) is predicted to occupy subpocket A, and R3 is predicted to occupy subpocket B.
Figure 3
Figure 3
Top view of the docking pose of compound 10 (in magenta) inside the binding site of the hA3AR model. Side chains of amino acids at the entrance of the binding site are highlighted and their Connolly surface is displayed. Surface color indicates hydrophobic regions (green), mildly polar regions (blue) and hydrogen bonding regions (magenta). Hydrogen atoms are not displayed.
Scheme 1
Scheme 1
Synthesis of N6-substituted 4′-truncated derivatives in the ring-constrained (N)- methanocarba adenosine series. Intermediate 22a was prepared as described. Reagents and conditions: (a) RNH2, Et3N, MeOH, rt; (b) Dowex50, MeOH/H2O, rt. Compound 24 was used for the following step without isolation.
Scheme 2
Scheme 2
Substitution of the C2 position of truncated nucleosides containing N6- dicyclopropylmethyl substitution, i.e. the most effective for preservation of hA1AR binding affinity, selectivity, and efficacy. Reagents and conditions: (a) RNH2, DIPEA, i-PrOH, reflux; (b) Dowex50, MeOH/H2O, rt; (c) hydrazine, reflux; (d) methoxycarbonyl malondialdehyde, EtOH, reflux; (e) 1 N NaOH, MeOH, rt.
Chart 1
Chart 1
Structures of representative 4′-truncated adenosine analogues and their receptor binding affinities in the series of 4′-thio-ribosides (1a, b) and ring-constrained (N)-methanocarba nucleosides (2a, b). Ki values in nM in binding to the hARs are indicated.,,,
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