NeuroAct Communication, Castres, France.
Psychopharmacology (Berl). 2011 Aug;216(4):451-73. doi: 10.1007/s00213-011-2247-y. Epub 2011 Mar 11.
There is increasing interest in antipsychotics intended to manage positive symptoms via D(2) receptor blockade and improve negative symptoms and cognitive deficits via 5-HT(1A) activation. Such a strategy reduces side-effects such as the extrapyramidal syndrome (EPS), weight gain, and autonomic disturbance liability.
This study aims to review pharmacological literature on compounds interacting at both 5-HT(1A) and D(2) receptors (as well as at other receptors), including aripiprazole, perospirone, ziprasidone, bifeprunox, lurasidone and cariprazine, PF-217830, adoprazine, SSR181507, and F15063.
We examine data on in vitro binding and agonism and in vivo tests related to (1) positive symptoms (e.g., psychostimulant-induced hyperactivity or prepulse inhibition deficit), (2) negative symptoms (e.g., phencyclidine-induced social interaction deficits and cortical dopamine release), and (3) cognitive deficits (e.g., phencyclidine or scopolamine-induced memory deficits). EPS liability is assessed by measuring catalepsy and neuroendocrine impact by determining plasma prolactin, glucose, and corticosterone levels.
Compounds possessing "balanced" 5-HT(1A) receptor agonism and D(2) antagonism (or weak partial agonism) and, in some cases, combined with other beneficial properties, such as 5-HT(2A) receptor antagonism, are efficacious in a broad range of rodent pharmacological models yet have a lower propensity to elicit EPS or metabolic dysfunction.
Recent compounds exhibiting combined 5-HT(1A)/D(2) properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT(1A) affinity and efficacy, which can markedly influence activity and side-effect profiles.
越来越多的人对旨在通过 D(2) 受体阻断来治疗阳性症状，通过 5-HT(1A) 激活来改善阴性症状和认知缺陷的抗精神病药物感兴趣。这种策略可以减少锥体外系综合征 (EPS)、体重增加和自主神经紊乱的副作用。
越来越多的人对旨在通过 D(2) 受体阻断来治疗阳性症状，通过 5-HT(1A) 激活来改善阴性症状和认知缺陷的抗精神病药物感兴趣。这种策略可以减少锥体外系综合征 (EPS)、体重增加和自主神经紊乱的副作用。
我们检查了与（1）阳性症状（例如，精神兴奋剂引起的过度活动或预脉冲抑制缺陷）、（2）阴性症状（例如，苯环利定引起的社交互动缺陷和皮质多巴胺释放）和（3）认知缺陷（例如，苯环利定或东莨菪碱引起的记忆缺陷）相关的体外结合和激动作用以及体内试验的数据。通过测量僵住和神经内分泌影响（通过确定血浆催乳素、葡萄糖和皮质酮水平）来评估 EPS 易感性。
具有“平衡”5-HT(1A) 受体激动作用和 D(2) 拮抗作用（或弱部分激动作用）的化合物，在某些情况下，与其他有益特性（如 5-HT(2A) 受体拮抗作用）相结合，在广泛的啮齿动物药理学模型中是有效的，但引发 EPS 或代谢功能障碍的可能性较低。
最近具有联合 5-HT(1A)/D(2) 特性的化合物可能在治疗更广泛的精神分裂症症状方面有效，并且比现有的抗精神病药物更耐受。然而，需要进一步研究来评估最近的化合物，特别是考虑到它们不同的 5-HT(1A) 亲和力和效力水平，这会显著影响活性和副作用谱。
