Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.
Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.
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发表时间：
1992-02
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通讯作者：
C. Bolden;B. Cusack;Elliott Richelson
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作者：
C. Bolden;B. Cusack;Elliott Richelson
我们测定了24种化合物：9种抗毒毒碱类药物（包括一些抗帕金森药物）和15种神经抑制剂（包括非典型化合物氯氮平、氟哌平、美尔培酮、利培酮、替尼拉平、硫osperone和佐替平）对中国仓鼠卵巢细胞中表达的5种人毒毒碱受体亚型的亲和力和结合选择性。平衡解离常数（Kd）是通过与[3H]喹啉苄基苯甲酸酯和这些细胞的膜制剂的竞争性放射配体结合研究获得的。正如预期的那样，QNB在5种受体亚型中具有最高的亲和力，并且没有选择性（Kd范围为0.027-0.088 nM）。苯托品对抗蛇毒化合物的亲和力次之，硫硝嗪对抗精神病药物的亲和力最高。在抗帕金森药物中，只有双剑藤对m1亚型有选择性；在抗精神病药中，非典型药物氯氮平对m1亚型也有选择性。这种选择性可以解释氯氮平对难治性精神分裂症患者的不同寻常的疗效和其锥体外系副作用的低发生率。然而，由于所研究的大多数其他非典型神经抑制剂对毒蕈碱受体亚型缺乏高亲和力和选择性，因此可能也涉及其他机制。
We determined the affinity and selectivity of binding for 24 compounds: nine antimuscarinics (including some antiparkinson drugs) and 15 neuroleptics (including the atypical compounds clozapine, fluperlapine, melperone, rilapine, risperidone, tenilapine, tiosperone and zotepine) at the five human muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Equilibrium dissociation constants (Kd) were obtained from competitive radioligand binding studies with [3H]quinuclidinyl benzilate and membranal preparations of these cells. As expected, QNB had the highest affinity of the compounds studied at the five receptor subtypes and was not selective (Kd ranged from 0.027-0.088 nM). Benztropine had the next highest affinity of the antimuscarinic compounds and thioridazine had the highest affinity of the neuroleptics. Among the antiparkinson drugs, biperiden was the only one selective for the m1 subtype; and among the neuroleptics, the atypical drug clozapine was also selective for the m1 subtype. This selectivity may explain clozapine's unusual efficacy in refractory schizophrenic patients and its low incidence of extrapyramidal side effects. However, because most other atypical neuroleptics studied lacked high affinity and selectivity at muscarinic receptor subtypes, it is likely that other mechanisms are involved as well.