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. Author manuscript; available in PMC: 2022 Mar 1.
Published in final edited form as: Biochem Pharmacol. 2021 Feb 3;185:114451. doi: 10.1016/j.bcp.2021.114451

Table 1: Structure-activity studies of 33 analogs in functional selectivity screens and SNAP-SCTR binding assays.

Average potencies (EC50 [μM] ± standard deviation (SD)) and average compound efficacy (Emax [%] ± SD) of compound dose response studies in screening mode. Compounds were tested in Cisbio GsD cAMP accumulation assays and SNAP-SCTR binding experiments; NT: not tested; n.d.: not detected (response less than mean ± 3xSD of negative control); data analysis via CBIS and Microsoft Excel; experiments were performed in duplicates in three to five independent experiments.

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Structural specifications SCTR PAM (3-pep mix) SCTR Sec-FL (PAM) SCTR agonist SNAP-SCTR Binding AVP PAM (AVP) GLP-1R PAM (GLP-1) GLP-1R agonist
CMPD ID R1 R2 R3 X n Y Ar EC50 [μM] Emax [%] EC50 [μM] Emax [%] EC50 [μM] Emax [%] EC50 [μM] Emax [%] EC50 [μM] Emax [%] EC50 [μM] Emax [%] EC50 [μM] Emax [%]
A1 OCH3 OCH3 H 3 3 NH graphic file with name nihms-1674663-t0013.jpg 7.7 ± 4.0 60 ± 16 8.5 ± 6.8 45 ± 14 34 ± 11 32 ± 5.4 6.3 ± 3.8 137 ± 11 19 ± 17 26 ± 11 12 ± 1.0 49 ± 21 22 ± 19 77 ± 51
A2 OCH3 OCH3 H 3 3 NH graphic file with name nihms-1674663-t0014.jpg 8.0 ± 4.4 72 ± 12 12 ± 13 55 ± 12 29 ± 16 26 ± 12 5.2 ± 1.2 144 ± 11 26 ± 20 26 ± 7.2 11 ± 5.3 57 ± 13 20 ± 14 70 ± 29
A3 H H OCH3 3 3 NH graphic file with name nihms-1674663-t0015.jpg 7.0 ± 3.9 40 ± 11 18 ± 22 21 ± 4.5 n.d. n.d. 11 ± 8.8 149 ± 23 n.d. n.d. 6.7 ± 3.5 62 ± 43 7.3 ± 4.7 48 ± 19
A4 OCH3 OCH3 H 3 3 NH graphic file with name nihms-1674663-t0016.jpg 7.7 ± 5.4 41 ± 1.3 12 ± 13 21 ± 3.3 26 ± 18 13 ± 2.9 6.8 ± 2.9 142 ± 5.9 n.d. n.d. 7.3 ± 4.7 58 ± 34 4.4 ± 1.9 46 ± 15
A5 OCH3 OCH3 H 3 3 NH graphic file with name nihms-1674663-t0017.jpg 8.4 ± 4.4 43 ± 15 15 ± 18 23 ± 3.2 26 ± 9.5 22 ± 6.1 3.4 ± 1.7 138 ± 10 38 ± 14 25 ± 6.5 5.4 ± 1.0 42 ± 18 6.2 ± 3.6 49 ± 15
A6 OCH3 OCH3 H 3 3 NH graphic file with name nihms-1674663-t0018.jpg 12 ± 5.3 77 ± 24 19 ± 11 61 ± 29 24 ± 7.9 25 ± 8.5 7.8 ± 3.0 148 ± 13 13 ± 13 26 ± 8.2 12 ± 1.6 61 ± 27 15 ± 2.3 61 ± 26
A7 OCH3 OCH3 H 3 3 NH graphic file with name nihms-1674663-t0019.jpg 8.4 ± 2.9 31 ± 5.0 12 ± 10 18 ± 3.9 45 ± 7.7 20 ± n.d. 3.2 ± 2.2 128 ± 15 46 ± 6.3 29 ± n.d. 28 ± 18 64 ± 30 9.5 ± 3.5 36 ± 14
A8 OCH3 OCH3 H 3 3 NH graphic file with name nihms-1674663-t0020.jpg 13 ± 5.5 63 ± 22 15 ± 12 30 ± 1.3 18 ± 0.6 27 ± 1.7 3.9 ± 2.7 128 ± 15 44 ± 4.0 52 ± 3.7 26 ± 13 57 ± 31 18 ± 13 56 ± 37
A9 H H OCH3 3 3 NH graphic file with name nihms-1674663-t0021.jpg 3.4 ± 1.7 42 ± 12 11 ± 19 38 ± 15 n.d. n.d. 6.8 ± 10 147 ± 30 n.d. n.d. 18 ± 22 48 ± 3.9 3.7 ± 1.9 32 ± 13
A10 H H OCH3 3 3 OH - 28 ± 16 20 ± 4.8 40 ± 14 6.6 ± n.d. n.d. n.d. n.d. n.d. 29 ± 21 14 ± n.d. n.d. n.d. 39 ± 8.3 26 ± 0.1
A11 F H H 2 ethyl - - n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. 38 ± 8.8 76 ± 1.6 42 ± 5.8 118 ± 15
A12 H H OCH3 3 methyl - - 18 ± 8.5 49 ± 18 28 ± 21 29 ± 3.3 n.d. n.d. 33 ± 24 104 ± n.d. 18 ± 13 16 ± 2.9 15 ± 11 71 ± 15 11 ± 6.1 75 ± 21
B1 OCH3 OCH3 CH3 - 1 - graphic file with name nihms-1674663-t0022.jpg 3.6 ± 0.6 47 ± 16 1.3 ± 0.3 33 ± 12 22 ± 19 16 ± 6.5 4.2 ± 2.8 160 ± 24 44 ± 8.6 31 ± n.d. 3.9 ± 1.0 32 ± 1.3 36 ± 14 20 ± n.d.
B2 OCH3 H CH3 - 1 - graphic file with name nihms-1674663-t0023.jpg 2.5 ± 0.5 93 ± 18 2.1 ± 0.9 34 ± 21 43 ± 14 15 ± n.d. 2.4 ± 0.3 172 ± 26 n.d. n.d. 23 ± 20 28 ± 4.3 n.d. n.d.
B3 H H H - 1 - graphic file with name nihms-1674663-t0024.jpg n.d. n.d. n.d. ± n.d. n.d. ± n.d. 37 ± 19 7.2 ± n.d. 0.7 ± 0.7 116 ±7.4 n.d. n.d. n.d. n.d. 42 ± 11 5.1 ± n.d.
B4 OCH3 H H - 1 - graphic file with name nihms-1674663-t0025.jpg 19 ± 12 23 ± 8.6 41 ± 13 16 ± n.d. 40 ± 15 20 ± n.d. 29 ± 8.1 144 ± 12 n.d. n.d. n.d. n.d. 42 ± 12 20 ± n.d.
B5 OCH3 H H - 2 - graphic file with name nihms-1674663-t0026.jpg 18 ± 23 26 ± 3.4 17 ± 23 31 ± 1.2 n.d. n.d. 0.4 ± 0.2 128 ± 11 n.d. n.d. 17 ± 23 30 ± 13 n.d. n.d.
B6 H H H - 1 - graphic file with name nihms-1674663-t0027.jpg 18 ± 23 20 ± 3.4 35 ± 21 29 ± n.d. n.d. n.d. 33 ± 24 130 ± n.d. n.d. n.d. n.d. n.d. n.d. n.d.
B7 H H H - 1 - graphic file with name nihms-1674663-t0028.jpg 19 ± 22 32 ± 1.6 34 ± 22 29 ± n.d. n.d. n.d. 6.4 ± 3.3 140 ± 24 n.d. n.d. 33 ± 24 29 ± n.d. n.d. n.d.
B8 Cl H H - 1 - graphic file with name nihms-1674663-t0029.jpg 18 ± 23 14 ± 1.6 35 ± 22 19 ± n.d. n.d. n.d. 1.0 ± 0.8 121 ± 9.2 n.d. n.d. n.d. n.d. n.d. n.d.
C1 OCH3 OCH3 H - 1 - graphic file with name nihms-1674663-t0030.jpg 6.9 ± 1.8 57 ± 11 8.3 ± 11 34 ± 13 42 ± 12 27 ± 1.1 2.8 ± 2.6 132 ± 12 n.d. n.d. 19 ± 22 54 ± 4.3 n.d. n.d.
C2 OCH3 H H - 1 - graphic file with name nihms-1674663-t0031.jpg 7.4 ± 0.8 37 ± 5.4 34 ± 23 20 ± n.d. 27 ± 14 17 ± 1.0 2.7 ± 2.2 131 ± 9.8 n.d. n.d. 19 ± 22 31 ± 9.2 n.d. n.d.
C3 OCH3 H H - 1 - graphic file with name nihms-1674663-t0032.jpg 7.9 ± 1.6 56 ± 11 13 ± 19 37 ± 14 39 ± 16 19 ± 0.9 5.5 ± 3.4 151 ± 11 n.d. n.d. 20 ± 21 29 ± 8.6 n.d. n.d.
C4 OCH3 OCH3 H - 1 - graphic file with name nihms-1674663-t0033.jpg 6.2 ± 1.0 76 ± 10 12 ± 19 38 ± 13 27 ± 19 20 ± 1.2 4.4 ± 1.8 147 ± 11 n.d. n.d. 20 ± 21 52 ± 2.7 46 ± 5.2 19 ± n.d.
C5 OCH3 OCH3 H - 1 - graphic file with name nihms-1674663-t0034.jpg 20 ± 0.3 71 ± 15 20 ± 17 27 ± 7.4 36 ± 11 27 ± 7.0 23 ± 11 165 ± 12 n.d. n.d. 22 ± 20 35 ± 0.8 41 ± 13 15 ± n.d.
C6 H OCH3 H - 1 - graphic file with name nihms-1674663-t0035.jpg 7.4 ± 2.0 62 ± 11 21 ± 23 36 ± 13 45 ± 8.6 17 ± 2.3 11 ± 15 152 ± 20 n.d. n.d. 19 ± 22 32 ± 10 n.d. n.d.
C7 H OCH3 H - 1 - graphic file with name nihms-1674663-t0036.jpg 8.2 ± 2.3 45 ± 1.6 34 ± 23 16 ± n.d. 36 ± 20 7.2 ± n.d. 5.0 ± 2.8 141 ± 9.0 n.d. n.d. 19 ± 22 37 ± 8.3 n.d. n.d.
C8 H H OCH3 - 1 - graphic file with name nihms-1674663-t0037.jpg 17 ± 8.7 39 ± 3.4 34 ± 23 14 ± n.d. 44 ± 8.3 15 ± n.d. 2.5 ± 2.1 135 ± 12 n.d. n.d. n.d. n.d. n.d. n.d.
C9 OCH3 OCH3 H - 1 - graphic file with name nihms-1674663-t0038.jpg 7.3 ± 3.2 67 ± 8.6 11 ± 19 37 ± 12 37 ± 17 23 ± 3.1 3.1 ± 2.4 140 ± 9.7 n.d. n.d. 2.4 ± 0.9 51 ± 7.4 39 ± 15 15 ± n.d.
C10 OCH3 OCH3 H - 1 - graphic file with name nihms-1674663-t0039.jpg 5.4 ± 0.6 84 ± 9.1 5.6 ± 4.8 48 ± 17 28 ± 22 15 ± 3.0 3.7 ± 1.0 155 ± 11 n.d. n.d. 2.6 ± 0.2 53 ± 16 n.d. n.d.
C11 H OCH3 H - 1 - graphic file with name nihms-1674663-t0040.jpg 5.4 ± 2.0 70 ± 4.0 33 ± 23 25 ± n.d. 19 ± 22 9.9 ± 2.1 5.2 ± 2.9 159 ± 12 n.d. n.d. 33 ± 17 46 ± n.d. 39 ± 15 6.8 ± n.d.
C12 H H H - 1 - graphic file with name nihms-1674663-t0041.jpg 21 ± 5.0 47 ± 12 34 ± 23 20 ± n.d. 37 ± 19 6.9 ± n.d. 22 ± 17 167 ± 13 n.d. n.d. 35 ± 21 34 ± n.d. n.d. n.d.
C13 H H H - 2 - graphic file with name nihms-1674663-t0042.jpg 5.7 ± 0.6 45 ± 19 19 ± 22 42 ± 3.3 n.d. n.d. 18 ± 23 113 ± 1.5 n.d. n.d. 18 ± 23 37 ± 15 n.d. n.d.
BETP - - - - - - - 24 ± 12 51 ± 25 31 ± 19 42 ± 2.0 n.d. n.d. 17 ± 14 152 ± 11 n.d. n.d. 0.8 ± 0.2 76 ± 22 0.8 ± 0.6 91 ± 16
Sec-FL [pM] - - - - - - - 0.5 ± 0.2 117 ± 11 0.4 ± 0.3 104 ± 4.4 0.5 ± 0.2 113 ± 8.3 3766 ±2300 104 ± 9.0 NT NT NT NT NT NT
GLP-1 [pM] - - - - - - - NT NT NT NT NT NT NT NT NT NT 0.6 ± 0.1 121 ± 5.3 0.6 ± 0.1 119 ± 6.8
AVP [pM] - - - - - - - NT NT NT NT NT NT NT NT 1.3 ± 0.3 109 ± 2.5 NT NT NT NT