. Author manuscript; available in PMC: 2018 Sep 14.

Published in final edited form as: J Med Chem. 2017 Aug 28;60(17):7459–7475. doi: 10.1021/acs.jmedchem.7b00805

Table 1.

Adiponectin-Secreting Activity of 1a and Related A₃ AR Ligands^a



							adiponectin (pg/mL)^c

compd	X	Y	R	K_i (hA₁AR) (nM)^b or % displacement at 1 µM	K_i (hA_2AAR) (nM)^b or % displacement at 1 µM	K_i (h_A3AR) (nM)^b or % displacement at 1 µM	20 µM	4 µM
A₃ AR agonists
1a	O	H	CH₃	51.2 ± 5.1	2910 ± 580	1.8 ± 0.7	216 ± 12^**	117 ± 20
1b	O	Cl	CH₃	222 ± 22	5360 ± 2470	1.4 ± 0.3	603 ± 10^**	221 ± 10^**
1c	S	H	CH₃	20.2 ± 2.9	475 ± 144	0.3 ± 0.1	343 ± 20^**	126 ± 14
1d	S	Cl	CH₃	193 ± 46	223 ± 36	0.38 ± 0.07	738 ± 59^**	131 ± 10
2a	S	H	CH₂CH₃	5.4 ± 0.3	57.6 ± 6.9	0.42 ± 0.22	242 ± 4^**	118 ± 38
2b	S	H	cyclopropyl	9.27 ± 0.83	15.2 ± 2.6	3.03 ± 0.23	249 ± 26^**	174 ± 5^**
2c	S	H	cyclopropyl-CH₂	159 ± 40	1600 ± 80	2.16 ± 0.29	490 ± 16^**	242 ± 11^**
2d	S	H	cyclobutyl	23.6 ± 4.2	122 ± 62	1.17 ± 0.16	633 ± 39^**	323 ± 30^**
A₃ AR antagonists
3a	S	Cl	3-I-Bn	2490 ± 940	341 ± 75	4.16 ± 0.5	857 ± 69^**	192 ± 19^*
3b	S	Cl	3-Cl-Bn	38%	18%	1.66 ± 0.9	442 ± 5^**	196 ± 1^**
3c	S	Cl	2-Cl-Bn	13%	1600 ± 135	25.8 ± 6.3	268 ± 14^**	107 ± 6
3d	S	H	3-Cl-Bn	860 ± 210	440 ± 110	1.5 ± 0.4	247 ± 7^**	163 ± 12^*
IDX control							100 ± 6
glibenclamide							1000 ± 193^**	838 ± 67^**

Results are the mean ± SD of three measurements using hBM-MSCs from three independent donors (n = 3, three independent experiments):

^(*)

p ≤ 0.05 and

^(**)

p ≤ 0.01.

Binding affinities of 1a and related A₃ AR ligands to human A₁, A_2A, and A₃ AR were previously reported.^27,29

In the IDX medium, 1a and related A₃ AR ligands were included to induce adipogenesis in hBM-MSCs. On the 7th day in culture, cell culture supernatants were harvested and ELISA was performed to measure levels of adiponectin.