Skip to main content
. Author manuscript; available in PMC: 2011 Jun 24.
Published in final edited form as: J Med Chem. 2010 Jun 24;53(12):4731–4748. doi: 10.1021/jm1003232

Table 1.

Inhibition of monoamine uptake and nAChR function for hydroxybupropion analogs

graphic file with name nihms210256u1.jpg
Compdc R1 R2 X Y Z monoamine uptake inhibitiona
 nAChR inhibitionb
IC50 (nM) IC50 (μM)
[3H]DA [3H]NE [3H]5HT α3β4* α4β2 α4β4 α1*β1
660 ± 178 1850 ± 300 IA 1.8 (1.15) 12 (1.15) 12 (1.07) 7.9 (1.12)
(2R,3R)-4a CH3 H Cl H H IA 9900 ± 1400 IA 6.5 (1.20) 31 (1.12) 41 (1.07) 7.6 (1.12)
(2S,3S)-4a CH3 H Cl H H 630 ± 50 241 ± 60 IA 11 (1.48) 3.3 (1.07) 30 (1.10) 28 (1.45)
4b CH3 H H H H 1065 ± 30 550 ± 90 IA 8.9 (1.23) 6.4 (1.23) 92 (1.29) IA
4c CH3 H F H H 1380 ± 360 740 ± 150 IA 15 (1.12) 1.3 (1.17) IA IA
4d CH3 H Br H H 3340 ± 680 920 ± 300 IA 3.2 (1.12) 0.55 (1.23) 30 (1.07) 18 (1.07)
4e CH3 H CH3 H H 2600 ± 400 1130 ± 20 IA 8.6 (1.12) 6.0 (1.20) 64 (1.20) 33 (1.07)
4f CH3 H CH3O H H 16,000 ± 2000 3000 ± 900 IA 11 (1.07) 10 (1.26) IA 49 (1.07)
4g CH3 H NO2 H H 12,000 ± 4000 1210 ± 340 IA 14 (1.10) 4.8 (1.26) 80 (1.10) 96 (1.10)
4h CH3 H H F H 4200 ± 700 3800 ± 600 IA 20 (1.15) 12 (1.10) IA 69 (1.17)
4i CH3 H H Cl H 285 ± 70 830 ± 90 4600 ± 900 5.1 (1.07) 9.2 (1.17) 33 (0.05) 19 (1.15)
4j CH3 H H CH3 H 832 ± 260 1680 ± 330 IA 8.6 (1.07) 12 (1.12) 62 (1.10) 20 (1.15)
4k CH3 H H CH3O H IA IA IA 11 (1.10) 27 (1.23) 72 (1.12) 25 (1.10)
4l CH3 H H C6H5 H IA 10,300 ± 1500 IA 1.3 (1.12) 1.8 (1.12) 8.1 (1.07) 5.9 (1.15)
4m CH3 H F F H 2140 ± 180 740 ± 110 IA 11.9 (1.15) 12 (1.07) IA 36 (1.2)
4nc CH3 H Cl Cl H 70 ± 20 114 ± 30 360 ± 40 2.6 (1.10) 20 (1.07) 14 (1.17) 7.2 (1.12)
4o CH3 H F H F 1020 ± 190 151 ± 43 IA 11 (1.15) 6.3 (1.51) 62 (1.07) 23 (1.12)
4pc CH3 H Cl H Cl 8250 ± 720 2440 ± 730 IA 3.9 (1.07) 11 (1.05) 18 (1.17) 7.2 (1.07)
4q CH3 H 1-napthyl — 10,000 ± 4000 411 ± 53 1565 ± 215 5.2 (1.15) 9.0 (1.07) 13 (1.10) 6.6 (1.10)
4r CH3 H 2-napthyl 453 ± 4 1570 ± 430 334 ± 42 2.0 (1.05) 6.5 (1.07) 11 (1.10) 11 (1.12)
4s C2H5 H Cl H H 204 ± 23 43.4 ± 72 2500 ± 540 4.3 (1.12) 2.9 (1.10) 16 (1.05) 14 (1.10)
4t C3H7 H Cl H H 30 ± 4 31 ± 10 4130 ± 770 4.8 (1.10) 7.5 (1.05) 18 (1.07) 10 (1.07)
4u CH3 CH3 Cl H H 3400 ± 600 415 ± 9 IA 6.5 (1.05) 7.1 (1.07) 43 (1.20) 57 (1.05)
4v CH3 CH3 H Cl H 2870 ± 820 527 ± 104 6480 ± 1280 4.6 (1.15) 42 (1.17) 91 (1.12) 43 (1.05)
5c IA IA IA IA IA IA IA
6c IA 7950 ± 1800 IA IA IA IA IA
a

Values for mean ± standard error of three independent experiments, each conducted with triplicate determination.

b

Mean micromolar IC50values (to two significant digits) for bupropion and the indicated analogs from three independent experiments for inhibition of functional responses to an EC80–EC90 concentration of carbamylcholine mediated by nAChR subtypes composed of the indicated subunits (where * indicates that additional subunits are or may be additional assembly partners with the subunits specified; see Methods and Materials). Numbers in parentheses indicate S.E.M. as a multiplication/division factor of the mean micromolar IC50 values shown [i.e., the value 1.8 (1.15) reflects a mean IC50 value of 1.8 μM with an S.E.M. range of 1.8 × 1.15 μM to 1.8/1.15 μM or 1.6–2.1 μM]. The value 11 (1.48) reflects a mean IC50 value of 11 μM with an S.E.M. range of 11 × 1.40 μM to 11/1.48 μM or 7.4–16 μM. IA: IC50 >100 μM.

c

Compounds 4b–4m, and 4o–4v are all (2S,3S)-isomers. Compounds 4n, 4p, 5, and 6 are racemic materials.