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. Author manuscript; available in PMC: 2011 Jun 7.
Published in final edited form as: J Med Chem. 2009 Dec 10;52(23):7580–7592. doi: 10.1021/jm900426g

Table 1. Potency of a Series of (N)-Methanocarba Adenosine Derivatives at Three Subtypes of Human ARs and the Functional Efficacy at the A3AR.

graphic file with name nihms294984u1.jpg
compd structure affinity (Ki, nM) or % inhibitiona % efficacy,b A3
R1 R2 A1 A2A A3
Series A
1ac Cl 3-Cl-Bn 260 ± 60h 2300 ±100 0.29 ± 0.04 103 ± 7
1b Cl 3-I-Bn 136 ± 22d,h 784 ± 97d 1.5 ± 0.2c 100c
3c H 3-I-Bn 700 ± 270h 6200 ± 100 2.4 ± 0.5 100
4c Cl cyclopentyl 18.3 ± 6.3h 3250 ± 300 3.7 ± 0.9 101
5 C≡C(CH2)2COOH 3-Cl-Bn (17 ± 4%) (24 ± 12%) 61.1 ± 35.8 106 ±18
6c,e C≡C(CH2)3COOH 3-Cl-Bn 14,900 ± 3500h (43%) 2.38 ± 0.56 ND
7 C≡C(CH2)4COOH 3-Cl-Bn (11 ± 5%) (38 ± 2%) 12.4 ± 1.8 74.4 ± 5.1
8 C≡C(CH2)2COOCH3 3-Cl-Bn (41 ± 0%) (43 ± 5%) 5.5 ± 0.3 90.0 ± 6.2
9c C≡C(CH2)3COOCH3 3-Cl-Bn 482 ± 23h (49%) 1.17 ± 0.27 ND
10 C≡C(CH2)4COOCH3 3-Cl-Bn (20 ± 7%) 3540 ± 1370 11.1 ± 2.3 85.0 ± 10.2
11 C≡C(CH2)2CONH(CH2)2NH2 3-Cl-Bn 2320 ± 520 550 ± 83 2.5 ± 0.5 96.9 ± 6.8
12c C≡C(CH2)3CONH(CH2)2NH2 3-Cl-Bn 454 ± 44h (81%) 2.17 ± 0.51 ND
13 C≡C(CH2)4CONH(CH2)2NH2 3-Cl-Bn (47 ± 3%) 277 ± 33 3.4 ± 0.7 100 ± 2
14 C≡C(CH2)2CONH(CH2)3NH2 3-Cl-Bn (31 ± 9%) 979 ± 181 3.1 ± 0.4 97.9 ± 18.4
15 C≡C(CH2)2CONH(CH2)4NH2 3-Cl-Bn (30 ± 2%) 766 ± 109 2.1 ± 0.4 102 ± 13
16 C≡C(CH2)2CO[NH(CH2)2]2NH2 3-Cl-Bn (33 ± 2%) 890 ± 110 15.4 ± 4.4 87.6 ± 21.2
17a C≡C(CH2)2CONH(CH2)2NH-biotin 3-Cl-Bn (1 ± 1%) (51 ± 2%) 36.4 ± 5.6 84.5 ± 12.0
17b C≡C(CH2)2CONH(CH2)2NH-CO(CH2)5NH-biotin 3-Cl-Bn (12 ± 4%) (47 ± 11%) 57.7 ± 16.2 107 ± 18
18 C≡C(CH2)2CONH(CH2)2NH-CO-(CH2)5Cy5g 3-Cl-Bn (36 ± 3%) 4730 ± 1020 17.2 ± 3.1 94.4 ± 9.6
Series B
19 C≡C(CH2)3COOH 3-Cl-Bn (0%) (9 ± 2%) 5270 ± 1090 ND
20 C≡C(CH2)2CONH(CH2)2NH2 3-Cl-Bn (33 ± 7%)h (8 ± 1%) (30 ± 1%) 25.6 ± 10.9
21 C≡C(CH2)4CONH(CH2)2NH2 3-Cl-Bn (36 ± 5%)h (5 ± 1%) 4630 ± 1060 52.0 ± 9.4
Series C
2ad Cl 3-Cl-Bn 3070 ± 1500h 4510 ± 910 1.06 ± 0.36 2.9 ± 3.7f
2bd,e Cl 3-Br-Bn 1760 ± 1010h 1600 ± 480 0.73 ± 0.30 46 ± 4,5.8 ± 0.8f
2cd,e Cl 3-I-Bn 3040 ± 610h 1080 ± 310 1.44 ± 0.60 44 ± 6, 1.0 ± 3.2f
22 H 3-Cl-Bn 1600 ± 150 4520 ± 830 4.9 ± 0.7 58.3 ± 8.0
23 H 3-I-Bn 839 ± 68 2330 ± 680 11.0 ± 2.2 80.8 ± 19.0
24 F 3-I-Bn 513 ± 4 4000 ± 780 10.7 ± 0.9 19.0 ± 3.0
25 Cl cyclopentyl 109 ± 16 1640 ± 360 120 ± 31 95.1 ± 4.6
26 C≡C(CH2)2CONH(CH2)2NH2 3-Cl-Bn (15 ± 2%) (35 ± 6%) 404 ± 67 0.9 ± 8.5
a

All experiments were done on CHO or HEK293 (A2A only) cells stably expressing one of four subtypes of human ARs. The binding affinity for A1, A2A, and A3ARs was expressed as Ki values (n = 3–5) and was determined by using agonist radioligands ([3H]51, [3H]54, or [125I]53, respectively), unless otherwise noted. A percent in parentheses refers to inhibition of radioligand binding at 10 μM.

b

Unless otherwise noted, the efficacy at the human A3AR was determined by inhibition of forskolin-stimulated cAMP production in AR-transfected CHO cells. At a concentration of 10 μM, in comparison to the maximal effect of 51 (= 100%) at 10 μM. Data are expressed as mean ± standard error (n = 3). ND, not determined.

c

Values from Melman et al.; Lee et al.; Tchilibon et al.15,16,21

d

Values from Melman et al.20

e

2b, MRS5147; 2c, MRS5127; 6, MRS5151.21,33

f

A3AR functional assay consisted of stimulation of [35S]GTPγS binding at 10 μM, expressed as a percentage of the full effect induced by 10 μM 51 (100 ± 5%).

g

Structure given in Scheme 1B.

h

A1AR binding determined using [3H]52.