Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.
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.
Department of Psychiatry, Mayo Clinic Jacksonville, Florida.
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Bolden
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Cusack
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Richelson
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D015152:Blotting, Northern; D016466:CHO Cells; D006224:Cricetinae; D015870:Gene Expression; D006801:Humans; D010276:Parasympatholytics / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D011869:Radioligand Assay; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000235:genetics
D014150:Antipsychotic Agents; D010276:Parasympatholytics; D012333:RNA, Messenger; D011950:Receptors, Cholinergic