An agonist of 5-HT7 receptors
LP-211 is an agonist of the serotonin (5-HT) receptor subtype 5-HT7 (Ki = 0.58 nM).1 It is selective for 5-HT7 over 5-HT1A and dopamine D2 receptors (Kis = 188 and 142 nM, respectively). It induces relaxation of isolated guinea pig ileum precontracted by substance P . LP-211 (100 nM) stimulates neurite outgrowth in primary murine striatal and cortical neurons.2
1.Leopoldo, M., Lacivita, E., De Giorgio, P., et al.Structural modifications of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides: Influence on lipophilicity and 5-HT7 receptor activity. Part IIIJ. Med. Chem.51(18)5813-5822(2008) 2.Lacivita, E., Podlewska, S., Speranza, L., et al.Structural modifications of the serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: A case studyEur. J. Med. Chem.120363-379(2016)
Kinase experiment: | Binding of [3H]-LSD at rat cloned 5-HT7 receptor is performed in the assay. In 1 mL of incubation buffer (50 mM Tris, 10 mM MgCl2 and 0.5 mM EDTA, pH 7.4) are suspended 30 μg of membranes, 2.5 nM [3H]-LSD, LP-211 (6?9 concentrations). The samples are incubated for 60 min at 37°C. The incubation is stopped by rapid filtration on GF/A glass fiber filters (presoaked in 0.5% polyethylenimine for 30 min). The filters are washed with 3 × 53 mL of ice-cold buffer (50 mM Tris, pH 7.4). Nonspecific binding is determined in the presence of 10 μM 5-CT. Approximately 90% of specific binding is determined under these conditions[1]. |
Animal experiment: | Rats[3]Thirty male adult Wistar rats (300-450 g) are assessed for novelty preference behavior after acute treatment (administered immediately after the training session and 24 h before the test session). After a 4 weeks' wash out, the rPDT is conducted to evaluate attraction from a greater/uncertain reward, with a sub-chronic treatment (five injections, immediately after sessions which follow the indifferent point). Food restriction, imposed by the experimenter through a limited quantity of food given at the end of each rPDT session, is applied to increase motivation to work for food delivery. All behavioral tests take place between 9:30 am and 4:00 pm. Rats are randomly assigned to treatment (LP-211 at 0.25 or 0.50 mg/kg i.p.) and control groups (injection volume 10 mL/kg; n?=?10 per group). The brain penetrant 5-HT7R agonist LP-211 is dissolved in a vehicle solution of 1% dimethyl sulfoxide (DMSO) in saline (0.9% NaCl). Control group receives the vehicle strictly in the same conditions[3]. |
参考文献: [1]. Leopoldo M, et al. Structural modifications of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides: influence on lipophilicity and 5-HT7 receptor activity. Part III. J Med Chem. 2008 Sep 25;51(18):5813-22. | |
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