Synthesis and biological evaluation of 2-aminothiazoles and their amide derivatives on human adenosine receptors. Lack of effect of 2-aminothiazoles as allosteric enhancers

doi:10.1016/j.bmc.2005.01.006

Bioorganic & Medicinal Chemistry

Volume 13, Issue 6, 15 March 2005, Pages 2079-2087

https://doi.org/10.1016/j.bmc.2005.01.006 Get rights and content

Abstract

A number of 2-aminothiazoles (2a–e) and their amide derivatives (4–10) were prepared. The 2-aminothiazoles themselves were tested as allosteric enhancers of agonist binding to human adenosine A₁ receptors. In a variety of experimental set-ups the compounds did not show any such effect, in contrast to earlier findings by another research group. Subsequently the 2-aminothiazoles were used as intermediates in the synthesis of a number of amide derivatives of either aromatic (4–6) or aliphatic nature (7–10). Some of the compounds emerged as moderately active antagonists on human adenosine A₁ and/or A_2A receptors with lower or negligible potency at adenosine A₃ receptors.

Graphical abstract

Introduction

Adenosine receptors are membrane-bound proteins belonging to the large family of G protein-coupled receptors. The four subtypes of adenosine receptors are the target for the endogenous ligand adenosine and as such they play an important role in intra- and intercellular communication. Their important role in physiology (e.g., in cardiac and metabolic homeostasis, in inflammation, and sleep/wake control mechanisms) has evoked the interest of medicinal chemists who, over the years, have generated a vast library of synthetic ligands interacting with these adenosine receptors.¹

Among these ligands an interesting class of the so-called ‘allosteric enhancers’ of adenosine binding and function at the adenosine A₁ receptor was discovered next to ‘classic’ agonists and antagonists. The reference compound is PD 81,723,² a 2-amino-3-aroylthiophene (1, Fig. 1), which served as a template for a range of related structures with similar characteristics.3, 4, 5, 6 Although the receptor binding site for these allosteric modulators has not been elucidated yet, it is believed that such compounds indeed bind to another site on the receptor than the primary ligand binding site for adenosine and synthetic derivatives thereof.

Interestingly, in a recent report a novel class of allosteric enhancers was identified. Certain 2-aminothiazoles were described to be potent enhancers of agonist binding surpassing the potency of PD 81,723 with 2 being the most active (Fig. 1).⁷ Our attention was drawn by these findings, also because we had previously reported on a series of functionalized 2-aminothiazoles as adenosine receptor antagonists (e.g., 3 in Fig. 1).⁸

We therefore decided to synthesize and study a number of known as well as new 2-aminothiazoles with respect to their activity on adenosine receptors, including hybrid structures of compounds 2 and 3. We were not able to confirm the allosteric enhancing capacity of the 2-aminothiazoles. Some of the compounds, however, proved to be antagonists for the adenosine receptors and showed affinity in the higher nanomolar range.

Section snippets

Chemistry

To prepare the compounds we applied a known synthetic route with minor modifications.7, 9 2-Aminothiazolium salts were prepared by a one-step synthesis from the appropriate ketones, thiourea, and iodine. 2-Aminothiazoles (2a–e) were obtained from the above HI salts after alkaline treatment. The syntheses of amide derivatives of 2-aminothiazoles (4a–e–6a–e; 7b–10b) were achieved by condensation reactions of 2-aminothiazoles (2a–e) with the appropriate acylchlorides either under classic⁸ or

Discussion

Recently 2-aminothiazoles were introduced as a new class of agonist allosteric enhancers of adenosine A₁ receptors.⁷ We first synthesized and analyzed such 2-aminothiazoles, both known (2a–c) and new derivatives (2d, 2e). At a concentration of 1 μM none of these five compounds appeared to affect significantly either radiolabeled antagonist ([³H]DPCPX) or radiolabeled agonist ([³H]CCPA) binding to the adenosine A₁ receptor. Particularly the lack of effect on [³H]CCPA binding surprised us, since

Conclusion

In our experiments 2-aminothiazoles (2a–e) did not behave as allosteric enhancers of agonist binding to adenosine A₁ receptors as suggested by Chordia et al.⁷ We therefore suggest to examine and reconsider the allosteric activity of this type of compounds. Amides derived from the 2-aminothiazoles (4–10) were also tested in radioligand binding studies and some of them proved to have modest affinity for adenosine A₁ and/or adenosine A_2A receptors. They were classified as antagonists based on the

Chemicals

[³H]DPCPX (128 Ci/mmol) and [¹²⁵I]AB-MECA (approx. 2000 Ci/mmol) were purchased from Amersham Pharmacia Biosciences (The Netherlands). [³H]CCPA (54.9 Ci/mmol) was obtained from NEN (The Netherlands). DPCPX and CPA were from Sigma-RBI (The Netherlands). [³H]ZM 241385 was obtained from Tocris Cookson (United Kingdom), [³H]cAMP was obtained from Perkin Elmer Life Sciences (The Netherlands). HEK 293 cells stably expressing the human adenosine A₃ receptor were a gift from Dr. K.-N. Klotz (University of

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Synthesis and biological evaluation of 2-aminothiazoles and their amide derivatives on human adenosine receptors. Lack of effect of 2-aminothiazoles as allosteric enhancers

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Discussion

Conclusion

Chemicals

J. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Am. Chem. Soc.

Curr. Top. Med. Chem.

International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

Pharmacol. Rev.

Allosteric Enhancement of Adenosine A1 Receptor Binding and Function by 2-Amino-3-benzoylthiophenes

Mol. Pharmacol.

Structure–Activity Relationships for Enhancement of Adenosine A1 Receptor Binding by 2-Amino-3-benzoylthiophenes

Mol. Pharmacol.

Allosteric Modulation of the Adenosine A1 Receptor. Synthesis and Biological Evaluation of Novel 2-Amino-3-benzoylthiophenes as Allosteric Enhancers of Agonist Binding

J. Med. Chem.

Allosteric Enhancement of Adenosine A₁ Receptor Binding and Function by 2-Amino-3-benzoylthiophenes

Structure–Activity Relationships for Enhancement of Adenosine A₁ Receptor Binding by 2-Amino-3-benzoylthiophenes

Allosteric Modulation of the Adenosine A₁ Receptor. Synthesis and Biological Evaluation of Novel 2-Amino-3-benzoylthiophenes as Allosteric Enhancers of Agonist Binding