Assié Marie-Bernadette, Dominguez Hélène, Consul-Denjean Nathalie, Newman-Tancredi Adrian
Neurobiology II, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106, Castres Cedex, France.
Naunyn Schmiedebergs Arch Pharmacol. 2006 Sep;373(6):441-50. doi: 10.1007/s00210-006-0092-z. Epub 2006 Sep 1.
Interaction with dopamine D2-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D2 receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [3H]nemonapride as a ligand. All the compounds reduced in vivo binding of [3H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D2 antagonists, nemonapride (ID50: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [3H]nemonapride binding. The 'atypical' antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D2-like receptors. New compounds, displaying marked agonism at 5-HT1A receptors in addition to D2 receptor affinity, exhibited varying D2 receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID50 values for inhibition of [3H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D2 receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID50 values herein and previously-reported ED50 values for catalepsy in mice. These data indicate that: (1) there is no difference in D2 receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D2 receptors can be dissociated from catalepsy, if the drugs also activate 5-HT1A receptors. Taken together, these data support the strategy of simultaneously targeting D2 receptor blockade and 5-HT1A receptor activation for new antipsychotics.
与多巴胺 D2 样受体的相互作用在抗精神病药物的治疗效果中起主要作用。我们在给予化合物 1 小时后，使用[3H]奈莫必利作为配体，检测了各种已确立的和潜在的抗精神病药物在小鼠纹状体和嗅结节中的体内多巴胺 D2 受体占有率。所有化合物均降低了纹状体中[3H]奈莫必利的体内结合。全身给药时，传统抗精神病药物、D2 拮抗剂、奈莫必利（ID50：0.034 mg/kg）、依替必利（0.047）、氟哌啶醇（0.11）和雷氯必利（0.11）能有效抑制[3H]奈莫必利结合。“非典型”抗精神病药物，利培酮（0.18）、齐拉西酮（0.38）、阿立哌唑（1.6）、奥氮平（0.99）和氯氮平（11.1）占据 D2 样受体的能力较弱。除了具有 D2 受体亲和力外，在 5-HT1A 受体上表现出显著激动作用的新化合物，其 D2 受体占有率各不相同：比氟普胺（0.25）、SLV313（0.78）、SSR181507（1.6）和沙立佐坦（6.7）。纹状体中抑制[3H]奈莫必利结合的 ID50 值与嗅结节中的值相关（r = 0.95，P < 0.0001）。这些值还与先前报道的化合物在大鼠 D2 受体上的体外亲和力相关（r = 0.85，P = 0.0001），以及与抑制小鼠阿扑吗啡诱导的攀爬相关（r = 0.79，P = 0.0005）。相比之下，本文中的 ID50 值与先前报道的小鼠僵住症 ED50 值之间没有显著相关性。这些数据表明：（1）大多数经典和非典型或潜在抗精神病药物在边缘区和纹状体区的 D2 受体占有率没有差异；（2）如果药物还激活 5-HT1A 受体，D2 受体的高占有率可以与僵住症分离。综上所述，这些数据支持了新抗精神病药物同时靶向 D2 受体阻断和 5-HT1A 受体激活的策略。
