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Abstract
(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel “atypical” antipsychotic drug which selectively binds to serotonin (5-HT2A, Ki=0.61 nM, 5-HT2C, Ki=20.7 nM) and dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10~100-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing (ED50=0.93 mg/kg) and DOI-induced head twitch (ED50=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose (ED50=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.
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Fig. 1.
Effects of YKP1447, olanzapine, risperidone, clozapine, quetiapine and aripiprazole on dextroamphetamine-induced hyperactivity in rats. The locomotor activity of dextroamphetamine was measured every 10 min for 1 h immediately after injection of amphetamine (1.5 mg/kg, i.p.). YKP1447 (a, top left panel), olnazapine (b, top right panel), risperidone (c, middle left), clozapine (d, middle right), quetiapine (e, bottom left) and aripiprazole (f, bottom right) or vehicle (Veh), administered (i.p.) 30 min before the injection of dextroamphetamine. The locomotor activities for 1 h are expressed as the total counts. Each value is mean±S.E.M. of seven to eight rats. ∗p<0.01, compared with vehicle-vehicle group (t-test), #p<0.05, when compared with amphetamine control group (the post-hoc test was Dunnett's multiple comparisons test).
Fig. 2.
Dose-response of YKP1447 (A), olanzapine (B), risperidone (C), clozapine (D), quetiapine (E) and aripiprazole (F) on CAR paradigm in rats. All drugs were administered i.p. (left panels) 30 min or p.o. (right panels) 60 min prior to test. Values are mean±S.E.M. (n=6~10) percentage avoidances compared to the preceding vehicle-day (e.g. pre-test), with each animal serving as their own control. Statistical analyses were performed by a one-way ANOVA with post hoc Dunnett's test. ∗p<0.05.
Fig. 3.
Effect of YKP1447, olanzapine, risperidone, clozapine, quetiapine and aripiprazole on induction of catalepsy in rats. Data are expressed as mean±S.E.M. ∗p<0.05 vs. vehicle (Veh)-treated group (the post hoc test was Dunnett's).
Table 1.
Effects of YKP1447, olanzapine, risperidone, clozapine, quetiapine and aripiprazole on apomorphine-induced climbing in mice
| ED50 (95% C.l.)∗ | ||
|---|---|---|
| mg/kg, ip | mg/kg, po | |
| YKP1447 | 0.93 (0.56~1.55) | 4.3 (4.0~4.7) |
| Olanzapine | 0.28 (0.11~0.72) | 1.2 (0.6~2.4) |
| Risperidone | 0.052 (0.03~0.1) | 0.052 (0.026~0.1) |
| Clozapine | 5.14 (4.36~6.06) | 6.74 (5.04~9.01) |
| Quetiapine | 3.9 (2.4~6.5) | 21.8 (20.1~23.5) |
| Aripiprazole | 0.3 (0.12~0.75) | 1.0 (0.93~1.07) |
Table 2.
Effects of YKP1447, olanzapine, risperidone, clozapine, quetiapine and aripiprazole on DOI-induced head twitch behavior in mice
| Treatment | ED50 (95% C.l.)∗ |
|---|---|
| mg/kg, ip | |
| YKP1447 | 0.18 (0.10~0.32) |
| Olanzapine | 0.024 (0.007~0.087) |
| Risperidone | 0.0054 |
| Clozapine | 0.56 (0.48~0.66) |
| Quetiapine | 2.45 (1.97~3.05) |
| Aripiprazole | 1.29 (1.02~1.64) |
Table 3.
Binding affinity (Ki to nM or % inhibition at 100 nM except M1 which is % inhibition at 1 μM) of YKP1447 for the various receptors. YKP1447 showed highly selective binding affinities to the 5-HT2A, 2C, D2 and 3 receptor subtypes
| 5HT1A | 5HT2A | 5HT2C | 5-HT3 | 5-HT4 | 5HT5A | 5HT6 | D1 | D2L | D2S | D3 | D4.2 | D4.4 | D5 | H1 | M1 | α1 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| YKP1447 | 2% | 0.61 | 20.7 | −15% | 9% | 1% | 9% | 4% | 45.9 | 44.5 | 42.1 | 6% | 12% | −5% | 2100 | 3% | 3,750 |
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