Quantitative structure-activity relationship study of human A₃ adenosine receptor antagonists: Derivatives of 2-aryl-1,2,4-triazolo[4,3-α]quinoxaline

Figures & data

Figure 1 Structure of 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones.

Figure 2 Structure of 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-4-amino-1-ones.

Table I.  QSAR parameters and binding activities of 2-aryl-1,2,4-triazolo[4,3-α]quinoxaline-1,4-diones (see Figure 1 for structure) at the human A₃ adenosine receptor.

				pKi(M)^a
No.	R	X	FR	Obsd.	Calc. Equation (2)	Prctd. LOO
1	OCH3	H	0.26	7.80	7.14	7.04
2	NO2	H	0.67	9.22	9.41	9.80
3	NH2	H	0.02	5.44	5.81	6.03
4	N(CH3)2	H	0.10	6.37	6.26	6.22
5	OC2H5	H	0.22	6.76	6.92	6.94
6	OH	H	0.29	7.33	7.31	7.30
7	OCOCH3	H	0.41	7.95	7.97	7.97
8	OCH3	NO2	0.26	8.33	–^b	–^b
9	OCH3	NH2	0.26	7.08	7.14	7.15

^a binding constant, K_i, represents the ability of a compound to displace [¹²⁵I]-N⁶-(4-amino-3-iodobenzyl)-5′-(N-methylcarbamoyl)adenosine ([¹²⁵I]AB-MECA) from cloned hA₃ receptor stably expressed in Chinese hamster ovary (CHO) cells; taken from Reference [12]

^b “outlier” compound in the present study.

Table II.  QSAR parameters and binding activities of 2-aryl-1,2,4-triazolo[4,3-α]quinoxalin-4-amino-1-ones (see Figure 2 for structure) at the human A₃ adenosine receptor.

				pKi(M)^a
No.	R	X	FR	Obsd	Calc. Equation (3)	Prctd. LOO
1	H	NO2	0.00	8.32	8.20	8.03
2	NH2	H	− 0.66	6.47	6.29	5.95
3	OH	H	− 0.37	7.14	7.13	7.13
4	OCH3	H	− 0.27	7.35	7.42	7.43
5	OCH3	NO2	− 0.27	7.33	7.42	7.44
6	OCH3	NH2	− 0.27	7.66	7.42	7.38
7	OH	NH2	− 0.37	6.75	7.13	7.20

^a,b See footnotes under Table I.

Table

			pKi (M)
R	X	FR	Calc., Equation (2)
NO	H	0.50	8.47
SO2CF3	H	0.73	9.74
SO2F	H	0.75	9.85
N(CH3)3	H	0.89	10.62

Table

			pKi(M)
R	X	σR	Calc., Equation(3)
OC2H5	H	− 0.24	7.51
OCOCH3	H	0.31	9.10
SO2CH3	H	0.72	10.28
SO2CF3	H	0.93	10.89
N(CH3)3	H	0.82	10.57

Figure 3 Plot of observed versus calculated and predicted pK_i values.

Colotta V, Catarzi D, Varano F, Calabri FR, Lenzi O, Filacchioni G, Martini C, Trincavelli L, Deflorian F, Moro S. J Med Chem 2004; 47: 3580–3590

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