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. Author manuscript; available in PMC: 2016 Jan 6.
Published in final edited form as: J Med Chem. 2015 May 7;58(10):4220–4229. doi: 10.1021/acs.jmedchem.5b00007

Table 1. Structure-Activity Relationship of the δ-PAM Chemotype in PathHunter CHO-OPRD1 and CHO-OPRM1 Cells in a β-Arrestin Recruitment Assaya.

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EC50 (μM) (% Ymax)
compd R1 R2 R3 δ μ selectivity μ/δ
1 H H H 0.2 (126) 6 (130) 30
2 (BMS-986187) CH3 H H 0.03 (124) 3 (121) 100
3 H CH3 H 0.2 (136) 3 (120) 15
4 H H CH3 0.3 (92) 4 (65) 13
5 F H H 0.1 (120) 5 (107) 50
6 H F H 1 (136) 7 (182) 7
7 H H F 0.1 (95) 2 (72) 20
8 Cl H H 0.3 (68) >10 (>100) >33
9 Cl Cl H 0.1 (116) >10 (>87) >100
10 (BMS-986188) Br H H 0.05 (58) >10 (>20) >200
11 OCHF2 H H 0.2 (109) 3 (80) 15
12 OCF3 H H 0.3 (114) 2 (111) 7
13 S02CH3 H H 0.9 (102) 5 (42) 6
14 CH2OH H H 1 (92) 10 (112) 10
15 CF3 H H >10 (>40) >10 (>20)
a

No activity was observed in agonist mode (in the absence of orthosteric agonist (data not shown)). In PAM mode (in the presence of an EC20 of leu-enkephalin for OPRD1 cells or an EC20 of endomorphin I for OPRM1 cells), robust responses were observed. The mean EC50 values, Ymax values, and potency ratio of δ receptor activity/μ receptor activity in PAM mode are reported in the table (n = 3).