Synthesis and biological effects of a new series of 2-amino-3-benzoylthiophenes as allosteric enhancers of A1-adenosine receptor

https://doi.org/10.1016/S0960-894X(00)00379-6Get rights and content

Abstract

New derivatives of PD 81,723, an allosteric enhancer of agonist binding to the A1-adenosine receptor, have been synthesized and evaluated in an intact cell assay. Compounds 3a, 3o and 3p appeared to be more potent than PD 81,723 and at a concentration of 0.1 μM caused significant reductions of cAMP content of CHO cells expressing the human A1-adenosine receptor. Compounds 4e and 4o appeared to be allosteric enhancers at a low concentration and antagonists at a higher concentration, whereas compounds 3c, 3g, 3s and 4l appeared to be weak antagonists that are also allosteric enhancers at the higher concentration of 10 μM.

Section snippets

Chemical Methods

The formation of 2-amino-3-benzoylthiophene from the base-catalyzed condensation of carbonyl compounds and nitriles, known as the ‘Gewald reaction’,6 was reported 35 years ago. Nevertheless, it was not until 1990 that synthesis of 2-amino-3-benzoylthiophenes by this method received renewed attention. The same method has been used for the synthesis of our new 2-amino-3-benzoylthiophene derivatives 3ax and 4av wherein the appropriate carbonyl compounds were reacted with benzoylacetonitrile

Biological Methods

Chinese hamster ovary cells expressing human recombinant A1-adenosine receptors (CHO: huA1 cells) at a density of approximately 8000 fmol/mg protein were prepared as previously described7 and aliquots of these cells at low passage numbers were frozen and stored in liquid nitrogen. Cells were removed from liquid nitrogen storage when needed, and grown in Ham's F-12 culture medium with 10% fetal bovine serum and 0.5 mg/ml of antibiotic G-418.8 Aliquots of cells were placed into 12-well culture

Results and Discussion

The effects of the newly-synthesized derivatives of PD 81,723 on CHO cells expressing the cloned human A1-adenosine receptor are shown in Table 2. Allosteric enhancers of agonist binding to the A1-adenosine receptor have been shown to increase agonist binding in equilibrium binding studies,2 to slow dissociation of the agonist-receptor complex in kinetic studies,2 and to cause leftward shifts of the agonist concentration-response relationship in studies of isolated tissues.7, 8 In the current

Acknowledgements

We wish to thank Medco Research for support of this research.

References (9)

  • V Ralevic et al.

    Pharmacol. Rev.

    (1998)
  • R.F Bruns et al.

    Mol. Pharmacol.

    (1990)
  • R.F Bruns et al.

    Mol. Pharmacol.

    (1990)
  • Baraldi, P. G. US Patent 5,939,432....
There are more references available in the full text version of this article.

Cited by (82)

  • Synthesis, single crystal, characterization and computational study of 2-amino-N-cyclopropyl-5-ethyl-thiophene-3-carboxamide

    2022, Journal of Molecular Structure
    Citation Excerpt :

    Moreover, sulfur-containing heterocyclic compounds have cleared the path for medicinal chemistry research. On the other hand thiophene derivatives, when combined with other heterocyclic ring systems, offer a broad range of medicinal uses, including antidepressants [2], analgesics [3], anti-inflammatory [4], anticancer [5], and anti-microbial properties [6]. Sulfur is an exceptionally cheap raw resource since it is a waste product generated by latest oil and gas refineries at a rate of 70 million tons per year.

  • TRR469, a potent A<inf>1</inf> adenosine receptor allosteric modulator, exhibits anti-nociceptive properties in acute and neuropathic pain models in mice

    2014, Neuropharmacology
    Citation Excerpt :

    Allosteric modulators of A1ARs, which act at a site distinct from the agonist binding site, could have potential therapeutic advantages over direct receptor agonists (Childers et al., 2005; Gao et al., 2005). After discovery of an initial such modulator 2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluromethyl)-phenyl]methanone (PD 81,723) (Bruns and Fergus, 1990), a wide range of A1AR positive allosteric modulators have been synthesized by different research groups (Baraldi et al., 2000, 2003, 2004; Lütjens et al., 2003; Romagnoli et al., 2006, 2008, 2012a, 2012b; Tranberg et al., 2002). Among the A1AR positive allosteric modulators, only 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)-(4-chlorophenyl)-methanone (T62) has been reported to produce anti-nociceptive effects reducing hypersensitivity (Li et al., 2002, 2003).

  • Allosteric modulation of A<inf>1</inf>-adenosine receptor: A review

    2013, Drug Discovery Today: Technologies
    Citation Excerpt :

    The compounds discovered by Bruns and coworkers have been shown to enhance adenosine binding and the functional activation of the A1-AR in heart and cardiovascular tissues, thus they could be useful both as antiarrythmic [47] and cardioprotective [48] agents. To study the role of various substitutions on the 3-aroyl moiety and the importance of the 4,5-dimethyl group on the thiophene ring, Bruns [43], Baraldi [49], Van der Klein and Kourounakis [50,51], Tranberg [52] and Lütjens [53] have directed significant effort to refining the SAR of the 3-, 4- and 5-positions of the 2-aminothiophene moiety (Fig. 1). Bruns et al. had previously reported that the lack of the 2-amino group resulted in a complete loss of activity, implying that this group was essential for activity [54].

View all citing articles on Scopus
View full text