Table 1.
Lobeline (1) and 10-O-carboxylic acid ester and sulfonic acid ester analogs (2–20) inhibition of [3H]NIC and [3H]MLA, [3H]MTBZ binding and [3H]DA and [3H]5-HT uptake into rat striatal and hippocampal synaptosomes, respectively.
| Compound | Ki μM (M ± SEM)a
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|---|---|---|---|---|---|
| [3H]MLA (α7*) | [3H]NIC (α4β2*) | [3H]DA (DAT) | [3H]5-HT (SERT) | [3H]MTBZ/DTBZ (VMAT2) | |
| Nicotine | 0.33 ±0.061 | 0.0014 ±0.00017 | – | – | – |
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| GBR 12909 | – | – | 0.018 ±0.0001c | – | – |
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| Fluoxetine | – | – | – | 0.041 ±0.0001c | – |
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| Tetrabenazine | – | – | – | – | 0.013 ±0.0001 |
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| Lobeline 1 | 6.26 ± 1.30 | 0.004 ± 0.001 | 28.2 ± 6.73 | 46.8 ± 3.70 | 5.46 ± 1.30b |
| 2 | > 100 | 2.87 ± 0.52 | 2.31 ±0.34 | 2.07 ± 0.51 | 1.53 ± 0.38 |
| 3 | > 100 | 1.62 ± 0.30 | 2.06 ± 0.12 | 1.51 ± 0.31 | 1.76 ± 0.54 |
| 4 | 18.4 ±0.42 | 19.3 ± 8.80 | 3.80 ± 0.35 | 2.04 ± 0.36 | 2.98 ± 0.21 |
| 5 | > 100 | 0.07± 0.01 | 4.64 ± 1.10 | 31.4 ± 17.4 | 8.05 ± 1.06 |
| 6 | 8.86 ± 2.36 | 0.15 ± 0.04 | 6.88 ± 1.20 | 4.87 ± 0.96 | 4.75 ± 0.92 |
| 7 | > 100 | 0.50 ± 0.08 | 4.82 ± 0.88 | 12.2 ± 3.10 | 3.38 ± 0.98 |
| 8 | > 100 | 0.06 ± 0.01 | 2.38 ± 0.20 | 1.06 ± 0.15 | 2.61 ± 0.52 |
| 9 | 36.2 ± 6.03 | 0.86 ± 0.26 | 3.02 ± 0.50 | 9.70 ± 1.50 | 6.37± 1.16b |
| 10 | 34.8 ± 1.13 | 0.008 ± 0.001 | 10.7 ± 1.30 | 37.3 ± 8.60 | 3.50 ± 0.80 |
| 11 | 18.0 ± 4.56 | 0.005 ± 0.001 | 29.1 ± 1.23 | 16.2 ± 3.40 | 10.8 ± 4.64 b |
| 12 | >100 | 0.016 ± 0.002 | 10.8 ± 1.80 | 4.38 ± 0.64 | 3.24 ± 0.28 |
| 13 | 24.2 ± 1.59 | 0.012 ± 0.002 | 17.9 ± 0.50 | 4.68 ± 0.67 | 3.00 ± 0.48 |
| 14 | 53.8 ± 10.4 | 0.013 ± 0.002 | 19.9 ± 2.80 | 18.1 ± 3.80 | 4.23 ± 1.08 |
| 15 | 53.8 ± 10.4 | 0.013 ± 0.002 | 19.9 ± 2.80 | 18.1 ± 3.80 | 4.23 ± 1.08 |
| 16 | 18.5 ± 3.06 | 0.010 ± 0.001 | 13.4 ± 0.30 | 5.06 ± 1.40 | 2.48 ± 0.33 |
| 17 | 47.7 ± 7.03 | 0.015 ± 0.002 | 4.60 ± 0.58 | 16.10 ± 1.40 | 2.09 ± 0.30 |
| 18 | 41.0 ± 15.4 | 0.011 ± 0.001 | 11.8 ± 0.50 | 5.16 ± 0.50 | 1.98 ± 0.65 |
| 19 | 46.6 ± 5.22 | 0.013 ± 0.001 | 14.7 ± 1.20 | 4.52 ± 0.37 | 3.98 ± 0.74 |
| 20 | >100 | 0.017 ± 0.002 | 4.14 ± 0.30 | 34.5 ± 3.70 | 4.12 ± 1.15 |
GBR-12909 (a specific DAT inhibitor), fluoxetine (a specific SERT inhibitor) and tetrabenazine (a specific VMAT2 inhibitor) were used as standards for comparison.
Ki values represent data from at least four independent experiments, each performed in duplicate.
Assays determining the Ki for lobeline using [3H]MTBZ and [3H]DTBZ as ligands revealed no significant difference (5.46 ± 1.3 vs 2.76 ± 0.64 μM, respectively). [3H]MTBZ was utilized as the ligand for analogs 2–9 and [3H]DTBZ was utilized as the ligand for analogs 10–20, since [3H]MTBZ was no longer available.