Rational for the design of the target compounds 3–7.

<p>Rational for the design of the target compounds 3–7.</p

Synthesis of desired compounds 3–7.

<p><i>Reagent</i>s: <b>i</b>: NH₂NH₂^.H₂O, EtOH, reflux, 3 days; <b>ii</b>: Ph₂O, 260°C, 2.5 h; <b>iii</b>: NH₂CN, pTsOH, 160°C, 4 h; <b>iv</b>: PhNCO, dioxane, reflux; <b>v</b>: RCOCl, Et₃N, dioxane, reflux.</p

Binding mode of xanthine-based compounds at the four AR subtypes.

<p>Compound <b>36</b>, in dark green, was selected as reference to show the proposed binding mode at the four AR subtypes. The crystallographic coordinates of caffeine, in magenta, bound to hA_2A AR are reported superimposed to the binding mode of compound <b>36</b>. The xanthine core of compound <b>36</b> is oriented in a similar manner to the crystallographic data. Residues particularly important in the binding are reported as light grey sticks.</p

Binding mode of compound 6 at the hA₃ AR.

<p>(A) (B) Hypothetical binding mode A and B of newly synthetized compounds to hA₃ AR. The most potent derivative, <b>6</b>, was selected as example and is represented as orange stick. Subsets of hA₃ AR residues, involved in the binding, are coloured in light grey. (C) The electrostatic and hydrophobic contributes to interaction energy calculated for the residue mostly involved in the binding are reported compound <b>6</b> in the conformation reported in panel A (in red) and B (in blue). Electrostatic energy values are expressed in kcal mol^–1, whereas hydrophobic scores are expressed in arbitrary hydrophobic units.</p

Discovery of 7‑(Prolinol‑<i>N</i>‑yl)-2-phenylamino-thiazolo[5,4‑<i>d</i>]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A_2A Adenosine Receptor: Prediction from Molecular Modeling

We describe the identification of 7-(prolinol-<i>N</i>-yl)-2-phenylamino-thiazolo­[5,4-<i>d</i>]­pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A_2A adenosine receptor (A_2AAR). Molecular-modeling indicated that the (<i>S</i>)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists’ ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A_2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties

Discovery of 7‑(Prolinol‑<i>N</i>‑yl)-2-phenylamino-thiazolo[5,4‑<i>d</i>]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A_2A Adenosine Receptor: Prediction from Molecular Modeling

We describe the identification of 7-(prolinol-<i>N</i>-yl)-2-phenylamino-thiazolo­[5,4-<i>d</i>]­pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A_2A adenosine receptor (A_2AAR). Molecular-modeling indicated that the (<i>S</i>)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists’ ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A_2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties

5′‑<i>C</i>‑Ethyl-tetrazolyl‑<i>N</i>⁶‑Substituted Adenosine and 2‑Chloro-adenosine Derivatives as Highly Potent Dual Acting A₁ Adenosine Receptor Agonists and A₃ Adenosine Receptor Antagonists

A series of <i>N</i>⁶-substituted-5′-<i>C</i>-(2-ethyl-2<i>H</i>-tetrazol-5-yl)-adenosine and 2-chloro-adenosine derivatives was synthesized as novel, highly potent dual acting hA₁AR agonists and hA₃AR antagonists, potentially useful in the treatment of glaucoma and other diseases. The best affinity and selectivity profiles were achieved by <i>N</i>⁶-substitution with a 2-fluoro-4-chloro-phenyl- or a methyl- group. Through an in silico receptor-driven approach, the molecular bases of the hA₁- and hA₃AR recognition and activation of this series of 5′-<i>C</i>-ethyl-tetrazolyl derivatives were explained

Structure-Based Design, Synthesis, and In Vivo Antinociceptive Effects of Selective A₁ Adenosine Receptor Agonists

Our previous work discovered that combining the appropriate 5′- and <i>N</i>⁶-substitution in adenosine derivatives leads to the highly selective human A₁ adenosine receptor (hA₁AR) agonists or highly potent dual hA₁AR agonists and hA₃AR antagonists. In order to explore novel dual adenosine receptor ligands, a series of <i>N</i>⁶-substituted-5′-pyrazolyl-adenosine and 2-chloro-adenosine derivatives were synthesized and assayed in vitro at all ARs. The <i>N</i>⁶-(±)-<i>endo</i>-norbornyl derivative <b>12</b> was the most potent and selective at A₁AR and effective as an analgesic in formalin test in mice, but none of the 5′-pyrazolyl series compounds showed a dual behavior at hA₁ and hA₃AR. Molecular modeling studies rationalized the structure–activity relationships and the selectivity profiles of the new series of A₁AR agonists. Interestingly, an unexpected inverted binding mode of the <i>N</i>⁶-tetrahydrofuranyl derivative <b>14</b> was hypothesized to explain its low affinity at A₁AR