Lu 38-012
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| Other names | LU-38012; LU38012 |
| Drug class | Dopamine D4 receptor antagonist |
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| Formula | C19H20ClN3 |
| Molar mass | 325.84 g·mol−1 |
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Lu 38-012 is a potent and selective dopamine D4 receptor antagonist which has been used in scientific research.[1][2] It has an affinity (Ki) for the dopamine D4.2 receptor of 7.5 nM and showed 16-fold selectivity for this receptor over the dopamine D2S receptor (Ki = 120 nM).[1] The drug had relatively little affinity for other dopamine receptors.[1] Affinities at other targets have also been reported.[1] The drug produces hypolocomotion and reverses dextroamphetamine- and phencyclidine (PCP)-induced hyperlocomotion without producing catalepsy in rodents.[1] Lu 38-012 partially substituted for clozapine in drug discrimination tests in rodents.[3][4] It was developed by Lundbeck and was first described in the scientific literature by 2006.[1][2][4]
See also
[edit]References
[edit]- 1 2 3 4 5 6 Hertel P, Didriksen M, Pouzet B, Brennum LT, Søby KK, Larsen AK, et al. (November 2007). "Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre-clinical antipsychotic potential". European Journal of Pharmacology. 573 (1–3): 148–160. doi:10.1016/j.ejphar.2007.06.052. PMID 17689529.
Lu 38-012 (5-[4- (4-chlorophenyl)piperazin-1-ylmethyl]-1H-indole (synthesised at H. Lundbeck A/S, Denmark) [...] In the course of a synthesis program, Lu 38-012 (Fig. 1) was subjected to a similar broad receptor profile (data not shown) and subsequent in vitro experiments (Tables 1–3) which showed that Lu 38-012 was a potent dopamine D4 receptor antagonist (Ki= 7.5 ± 0.4 nM) with at least 15-fold lower activity at the targets detailed above. This compound was used along with the selective dopamine D4 ligands, L-745,870 (Patel et al., 1997) and sonepiprazole (Merchant et al., 1996) to delineate the behavioural consequences of D4 receptor blockade. [...] The selective dopamine D4 receptor ligands Lu 38-012 and L745,870 reduced the hyperactivity induced by a low dose of Damphetamine (0.5 mg/kg, s.c.) but were both less potent in inhibiting PCP-induced hyperactivity. In fact, L-754,870 failed to reach an ED50 value for inhibiting the hyperactivity induced by PCP at doses up to 40 mg/kg s.c. (Table 4). The selective dopamine D4 receptor antagonist sonepiprazole was inactive on both these measures at doses up to 40 mg/kg. [...] The involvement of dopamine D4 receptor in this context is also supported by the ability of the selective dopamine D4 receptor antagonist Lu 38-012 to mimic the behavioural effects of Lu 35-138. [...]
- 1 2 Hertel P (December 2006). "Comparing sertindole to other new generation antipsychotics on preferential dopamine output in limbic versus striatal projection regions: mechanism of action". Synapse. 60 (7). New York, N.Y.: 543–552. doi:10.1002/syn.20322. PMID 16952163.
- ↑ Prus AJ, Wise LE, Pehrson AL, Philibin SD, Bang-Andersen B, Arnt J, et al. (October 2016). "Discriminative stimulus properties of 1.25mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors". Brain Research. 1648 (Pt A): 298–305. doi:10.1016/j.brainres.2016.08.004. PMID 27502027.
Partial substitution occurred with the D4 receptor antagonist Lu 38-012 [...] the D4 receptor antagonist Lu 38- 012 also produced partial substitution at the 5.0 mg/kg dose (60.9% ± SEM=12.9). [...] partial stimulus generalization occurred to the D4 receptor antagonist Lu 38-012 [...] As noted earlier partial substitution occurred with the selective D4 receptor antagonist Lu 38-012 [...] Taking these findings together, D4 receptor antagonism may represent part of the clozapine discriminative cue, which has long been considered a compound stimulus (Goudie et al. 1998). [...] No substitution occurred for Lu 35-138, which also is an antagonist for D4 receptors and α1 adrenoceptors, but this compound also inhibits 5-HT reuptake (Hertel et al. 2007). Enhanced 5-HT concentrations produced by Lu 35-138 may run counter to clozapine's pharmacological profile by activating, rather than blocking, 5-HT2 receptors.
- 1 2 Prus AJ, Philibin SD, Pehrson AL, Porter JH (March 2006). "Discriminative stimulus properties of the atypical antipsychotic drug clozapine in rats trained to discriminate 1.25 mg/kg clozapine vs. 5.0 mg/kg clozapine vs. vehicle". Behavioural Pharmacology. 17 (2): 185–194. doi:10.1097/01.fbp.0000197457.70774.91. PMID 16495726.
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