Kehne J H, Baron B M, Carr A A, Chaney S F, Elands J, Feldman D J, Frank R A, van Giersbergen P L, McCloskey T C, Johnson M P, McCarty D R, Poirot M, Senyah Y, Siegel B W, Widmaier C
Hoechst Marion Roussel, Inc., Cincinnati, Ohio, USA.
J Pharmacol Exp Ther. 1996 May;277(2):968-81.
In preclinical studies, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol] [formula: see text] (MDL 100,907), a putative atypical antipsychotic, was characterized in vitro as a potent and selective ligand for the serotonin2A (5-HT2A) receptor and was evaluated in vitro and in vivo as a potent 5-HT2A receptor antagonist. Furthermore, MDL 100,907's potential CNS safety profile and selectivity as a potential antipsychotic agent were evaluated and compared with benchmark compounds. MDL 100,907 demonstrated low nanomolar or subnanomolar binding in vitro at the 5-HT2A receptor and showed a > 100-fold separation from all other receptors measured. MDL 100,907 had subnanomolar potency as a 5-HT2A antagonist in vitro in reversing 5-HT-stimulated inositol phosphate accumulation in NIH 3T3 cells transfected with the rat 5-HT2A receptor. In vivo, MDL 100,907 potently inhibited 5-methoxy-N, N-dimethyltryptamine-induced head twitches in mice or 5-hydroxytryptophan-induced head twitches in rats. In vivo functional tests in mice revealed a > 500-fold separation between doses that produced 5-HT2A antagonism and doses that produced alpha 1-adrenergic or striatal D2 antagonism. Using inhibition of D-amphetamine-stimulated locomotion in mice as a measure of potential antipsychotic efficacy, MDL 100,907 showed a superior CNS safety index relative to the reference compounds, haloperidol, clozapine, risperidone, ritanserin, and amperozide, in each of five tests for side effect potential, including measures of ataxia, general depressant effects, alpha 1-adrenergic antagonism, striatal D2 receptor antagonism, and muscle relaxation. MDL 100,907 did not antagonize apomorphine-induced stereotypes in rats, suggesting that it potentially lacks extrapyramidal side effect liability. MDL 100,907 showed selectivity as a potential antipsychotic in that it lacked consistent activity in selected rodent models of anticonvulsant, antidepressant, analgesic, or anxiolytic activity. In summary, these preclinical data indicate that MDL 100,907 is a potent and selective ligand at the 5-HT2A receptor. MDL 100,907's potent 5-HT2A antagonist activity might account for its activity in preclinical models of antipsychotic potential. Ongoing clinical evaluation with MDL 100,907 will test the hypothesis that 5-HT2A receptor antagonism is sufficient for antipsychotic activity in humans.
在临床前研究中，[R-(+)-α-(2,3-二甲氧基苯基)-1-[2-(4-氟苯基)乙基]-4-哌啶甲醇] [化学式：见正文] (MDL 100,907)，一种假定的非典型抗精神病药物，在体外被表征为血清素2A (5-HT2A) 受体的强效和选择性配体，并在体外和体内被评估为强效的5-HT2A受体拮抗剂。此外，评估了MDL 100,907作为潜在抗精神病药物的潜在中枢神经系统安全性概况和选择性，并与基准化合物进行了比较。MDL 100,907在体外对5-HT2A受体表现出低纳摩尔或亚纳摩尔结合，并与所测量的所有其他受体显示出超过100倍的分离度。MDL 100,907在体外作为5-HT2A拮抗剂具有亚纳摩尔效力，可逆转在用大鼠5-HT2A受体转染的NIH 3T3细胞中5-羟色胺刺激的肌醇磷酸积累。在体内，MDL 100,907有效抑制小鼠中5-甲氧基-N, N-二甲基色胺诱导的头部抽搐或大鼠中5-羟色氨酸诱导的头部抽搐。在小鼠中的体内功能测试显示，产生5-HT2A拮抗作用的剂量与产生α1-肾上腺素能或纹状体D2拮抗作用的剂量之间存在超过500倍的分离度。使用抑制小鼠中D-苯丙胺刺激的运动作为潜在抗精神病疗效的指标，在五项副作用潜力测试中的每一项中，包括共济失调、全身抑制作用、α1-肾上腺素能拮抗作用、纹状体D2受体拮抗作用和肌肉松弛的测量，MDL 100,907相对于参考化合物氟哌啶醇、氯氮平、利培酮、利坦色林和氨哌齐特显示出更高的中枢神经系统安全指数。MDL 100,907不会拮抗大鼠中阿扑吗啡诱导的刻板行为，表明它可能没有锥体外系副作用倾向。MDL 100,907作为潜在抗精神病药物表现出选择性，因为它在选定的抗惊厥、抗抑郁、镇痛或抗焦虑活性的啮齿动物模型中缺乏一致的活性。总之，这些临床前数据表明MDL 100,907是5-HT2A受体的强效和选择性配体。MDL 100,907的强效5-HT2A拮抗剂活性可能解释了其在抗精神病潜力临床前模型中的活性。正在进行的MDL 100,907临床评估将检验5-HT2A受体拮抗作用足以产生人类抗精神病活性这一假设。
