1,2,4-Triazolo[4,3- a ]quinoxalin-1-one: A Versatile Tool for the Synthesis of Potent and Selective Adenosine Receptor Antagonists

University of Florence, Florens, Tuscany, Italy
Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2000; 43(6):1158-64. DOI: 10.1021/jm991096e
Source: PubMed


4-Amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4, 3-a]quinoxalin-1-one (1) has been found to be an A(2A) versus A(1) selective antagonist (Colotta et al. Arch. Pharm. Pharm. Med. Chem. 1999, 332, 39-41). In this paper some novel triazoloquinoxalin-1-ones 4-25 bearing different substituents on the 2-phenyl and/or 4-amino moiety of the parent 4-amino-1, 2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (3) have been synthesized and tested in radioligand binding assays at bovine A(1) and A(2A) and cloned human A(3) adenosine receptors (AR). Moreover, the binding activities at the above-mentioned AR subtypes of the 1,4-dione parent compounds 26-31 and their 5-N-alkyl derivatives 33-37 were also evaluated. The substituent on the 2-phenyl ring exerted a different effect on AR subtypes, while replacement of a hydrogen atom of the 4-amino group with suitable substituents yielded selective A(1) or A(3) antagonists. Replacement of a hydrogen atom of the 4-NH(2) with an acyl group, or replacement of the whole 4-NH(2) with a 4-oxo moiety, shifted the binding activity toward the A(3) AR. The binding results allowed elucidation of the structural requirements for the binding of these novel tricyclic derivatives at each receptor subtype. In particular, A(1) and A(2A) binding required the presence of a proton donor group at position-4, while for A(3) affinity the presence of a proton acceptor in this same region was of paramount importance.

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Available from: Vittoria Colotta, Aug 31, 2015
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    • "High affinity adenosine receptor antagonists with at least 50-fold selectivity for each of the AR subtypes were collected from literature (see Supplementary Materials). The ligand set includes preclinical and clinical candidates listed in a recent review (Jacobson and Gao, 2006), a diverse set of A 2A AR selective compounds from ref (Mantri et al., 2008), as well as several series of AR binding compounds for A 1 AR (van Veldhoven and Chang, 2008; Colotta et al., 2000), A 3 AR (Baraldi et al., 2003), and A 2B AR (Stefanachi et al., 2008a; Kalla and Zablocki, 2009), Fig. 1. Residue variations in the ligand binding pocket between four human adenosine receptor subtypes. "
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    ABSTRACT: In a recent paper (Colotta et al. J. Med. Chem. 2000, 43, 1158-1164) we reported the synthesis and adenosine receptor binding activity of two sets of 2-aryl-1,2,4-triazolo[4,3-a]quinoxalines (A and B) some of which were potent and selective A(1) or A(3) antagonists. In this paper the synthesis of a set of 2-arylpyrazolo[3,4-c]quinolin-4-ones 1-10, 4-amines 11-18, and 4-amino-substituted derivatives 19-35 are reported. The binding activity at bovine A(1) and A(2A) and human cloned A(3) adenosine receptors showed that (i) the substituent on the appended 2-phenyl ring could be used to modulate A(1) and A(3) affinity, (ii) the 4-amino group was necessary for A(1) and A(2A) binding activity, and (iii) a nuclear or extranuclear C=O proton acceptor at position 4 yielded potent and selective A(3) antagonists. These results are in agreement with those of the previously reported series A and B suggesting a similar adenosine receptor binding mode. In particular, the A(3) nanomolar affinity of 1-8, 31-33, and 35 confirms the hypothesis of the presence in the N-6 region of the adenosine A(3) subtype of a proton donor able to bind to a C=O proton acceptor at position 4.
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