CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
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CEP-26401 (Irdabisant)，一种有效的选择性组胺 H3 受体拮抗剂/反向激动剂，具有认知增强和唤醒活性
DOI：
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发表时间：
2012
影响因子：
3.5
通讯作者：
M. Williams
中科院分区：
文献类型：
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作者：
R. Raddatz;R. Hudkins;J. Mathiasen;John A. Gruner;D. Flood;L. Aimone;Siyuan Le;H. Schaffhauser;E. Duzic;M. Gąsior;D. Bozyczko‐Coyne;M. Marino;M. Ator;E. Bacon;J. Mallamo;M. Williams
CEP-26401 [irdabisant; 6-{4-[3-（（R）-2-甲基-吡咯烷-1-基）-丙氧基]-苯基}-2H-哒嗪-3-酮HCl]是一种新型、强效组胺H3受体（H3 R）拮抗剂/反向激动剂，具有药物样性质。在大鼠脑细胞膜（Ki = 2.7 ± 0.3 nM）以及重组大鼠和人H3 R表达系统（Ki分别为7.2 ± 0.4和2.0 ± 1.0 nM）中，在放射性配体结合置换试验中证明了CEP-26401对H3 R的高亲和力。CEP-26401在[35 S]鸟苷5′-O-（γ-硫代）三磷酸结合试验中显示出有效的拮抗剂和反向激动剂活性。口服CEP-26401后，通过大鼠皮质切片中离体结合的抑制来估计H3 R的占有率（OCC 50 = 0.1 ± 0.003 mg/kg），并在相似的剂量范围内（ED 50 = 0.06 mg/kg）证实了大鼠致渴模型中H3 R激动剂R-α-甲基组胺诱导的饮水反应的拮抗作用。CEP-26401在0.01至0.1 mg/kg p.o.剂量下改善了短期记忆的大鼠社会识别模型中的表现。并且在3至30 mg/kg p.o.在DBA/2NCr 1小鼠中，CEP-26401以10和30 mg/kg i. p.增加前脉冲抑制（PPI），而抗精神病药利培酮以0.3和1 mg/kg i. p.有效。PPI增加。这些结果证明CEP-26401在啮齿动物模型中的有效行为作用，并表明这种新型H3 R拮抗剂在治疗认知和注意力障碍中可能具有治疗效用。CEP-26401也可用于治疗精神分裂症或作为获批抗精神病药物的后续治疗。
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (Ki = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (Ki = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [35S]guanosine 5′-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.
精神分裂症的自发选择性注意。
影响因子：
11.3
作者：
Myles-Worsley,M;Johnston,WA;Wender,PH
通讯作者：
Wender,PH