5. In Vitro Receptor Functional and Binding Data and Cell Permeability and In Vivo Data for Chiral 7-Substituted 8‑Carboxamide Analogues 19.
| 5-HT2CR |
5-HT2BR |
5-HT2AR |
Cell
Permeability
|
Inhibition
of Food Intake at 1 h (%) |
Abbreviated
CNS PK Study (10 mg/kg PO) Tissue Concentrations
at 1 h |
|||||
|---|---|---|---|---|---|---|---|---|---|---|
| Compound | EC50, nM (E max, %, n) | Ki, nM (n) | Ki, nM (n) | Ki, nM (n) | A-B (×10–6 cm s–1) | Efflux ratio | 10 mg/kg PO screen | ED50 (mg/kg po) | Plasma (ng/mL) | Brain (ng/g) |
| (+)-19a | 11.5 (106, 25) | 19.2 (18) | 4240 (12) | 1270 (17) | 14.85 | 2.40 | 83 (41) | 5.2 | 1660 | 440 |
| (−)-19a | >25,000 (n.m., 6) | 10,000 (2) | >50,000 (2) | >50,000 (2) | n.d. | n.d. | 0 | n.d. | n.d. | n.d. |
| (+)-19c | 22.5 (107, 3) | 33.4 (3) | >50,000 (3) | 7270 (3) | n.d. | n.d. | 53 | n.d. | n.d. | n.d. |
| (+)-19i | 52 (105, 20) | 38 (13) | >50,000 (113) | 9250 (12) | 7.73 | 3.79 | 63 | 6.4 | 1010 | 222 |
| (−)-19i | >25,000 (n.m., 9) | 5570 (4) | >50,000 (4) | >50,000 (4) | n.d. | n.d. | 0 | n.d. | n.d. | n.d. |
| (+)-19k | 8 (112, 12) | 17.6 (15) | >50,000 (14) | 23,800 (12) | 12.8 | 2.16 | 27 | >5 | 866 | 454 |
| (+)-19m | 42 (112, 23) | 39 (27) | >50,000 (23) | >50,000 (26) | 8.9 | 1.9 | 81 | 2.8 | 960 | 832 |
a
[125I]-DOI ligand.
b
In P-gp-expressing LLCPK2 cells.
c
Mean of two determinations.
d
5 mg/kg dose. [125I]-DOI: [125I]-2,5-dimethoxy-4-iodoamphetamine. CNS: central nervous system. ED50: effective dose for 50% of the population. n.d.: not determined. n.m.: not measurable. PK: pharmacokinetic. PO: oral administration.