Table 1.

Potency of a series of nucleoside-dendrimer conjugates at three subtypes of human ARs.

Compd	Structure, R1, R2, or R3	Affinity (Ki, nM) or % inhibitiona
		A1	A2	A3
Model compounds
1b IB-MECA		51	2900	1.8
2b,c	R1 = Cl	260±60h	2300±100	0.29±0.04
3ab,c	R1 = C≡C(CH2)4C≡CH	(31±2%) at 10 μM	7040±143 0	29.4±9.8
4ab,c	R2 = (CH2)2NHCOCH3	(12±4%) at 10 μM	2440±320	22.3±1.6
4bb	R1 = C≡C(CH2)2CH3	1040±80	(80%) at 10 μM	0.82±0.20
4cb	R3 = C≡C(CH2)4CONH(CH2)2NHCOCH3	181±22	(80%) at 10 μM	2.88±0.54
Dendrimer derivatives
5d		NA	NA	NA
6c	64	22.6±6.9	32.2±6.4	0.14±0.09
7c	24 28	35.1±7.5	34.4±1.8	0.32±0.03
8c	31 33	78±31	584±48	39.5±11.8
9	8	ND	(27±7%) at 10 μM	31.4±2.8
10	5	77	(3±2%) at 1 μM	41.7±6.4
11c	13	7.1	5750±1600	17.6±2.8
12	64	1.92±1.25	727±168	11.8±2.2

^aAll experiments were done on CHO or HEK293 (A_2A only) cells stably expressing one of four subtypes of human ARs. The binding affinity for A₁, A_2A, and A₃ARs was expressed as K_i values (n = 3–5) and was determined by using agonist radioligands ([³H]NECA, [³H]CGS21680, or [¹²⁵I]I-AB-MECA, respectively), unless noted. A percentage in parentheses refers to inhibition of radioligand binding at the indicated concentration. The concentrations of the dendrimer-ligand complexes were measured by the concentration of the dendrimer, not the ligand. Therefore, all binding K_i values of dendrimers are expressed as K_iapp values.

^bAffinity values from Tosh et al. (15, 21) and Melman et al. (14).

^c2, MRS3558; 3a, MRS5221; 4a, MRS5233; 6, MRS5246; 7, MRS5247; 8, MRS5259; 11, MRS5216.

^dCoumpound 5 is the dendrimer precursor of 8 and is similar to the dendrimer precursor of 6 and 7.

NA – not active in inhibition of radioligand binding (<10%) at 1 μM.