Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.

Article Details

Citation

Bolden C, Cusack B, Richelson E

Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.

J Pharmacol Exp Ther. 1992 Feb;260(2):576-80.

PubMed ID
1346637 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BiperidenMuscarinic acetylcholine receptor M1Ki (nM)0.48N/AN/ADetails
ChlorpromazineMuscarinic acetylcholine receptor M1Ki (nM)25N/AN/ADetails
ChlorpromazineMuscarinic acetylcholine receptor M3Ki (nM)67N/AN/ADetails
ChlorprothixeneMuscarinic acetylcholine receptor M1Ki (nM)11N/AN/ADetails
ChlorprothixeneMuscarinic acetylcholine receptor M2Ki (nM)28N/AN/ADetails
ChlorprothixeneMuscarinic acetylcholine receptor M3Ki (nM)22N/AN/ADetails
ChlorprothixeneMuscarinic acetylcholine receptor M4Ki (nM)18N/AN/ADetails
ClozapineMuscarinic acetylcholine receptor M1Ki (nM)3.1N/AN/ADetails
ClozapineMuscarinic acetylcholine receptor M2Ki (nM)48N/AN/ADetails
ClozapineMuscarinic acetylcholine receptor M3Ki (nM)20N/AN/ADetails
ClozapineMuscarinic acetylcholine receptor M4Ki (nM)11N/AN/ADetails
DiphenhydramineMuscarinic acetylcholine receptor M2Ki (nM)120N/AN/ADetails
LoxapineMuscarinic acetylcholine receptor M1Ki (nM)63.9N/AN/ADetails
LoxapineMuscarinic acetylcholine receptor M2Ki (nM)300N/AN/ADetails
LoxapineMuscarinic acetylcholine receptor M3Ki (nM)390N/AN/ADetails
LoxapineMuscarinic acetylcholine receptor M4Ki (nM)300N/AN/ADetails
PirenzepineMuscarinic acetylcholine receptor M1Ki (nM)8N/AN/ADetails
ProcyclidineMuscarinic acetylcholine receptor M1Ki (nM)4.6N/AN/ADetails
ProcyclidineMuscarinic acetylcholine receptor M2Ki (nM)25N/AN/ADetails
ProcyclidineMuscarinic acetylcholine receptor M3Ki (nM)12.4N/AN/ADetails
ProcyclidineMuscarinic acetylcholine receptor M4Ki (nM)7N/AN/ADetails
ScopolamineMuscarinic acetylcholine receptor M1Ki (nM)1.1N/AN/ADetails
ScopolamineMuscarinic acetylcholine receptor M2Ki (nM)0.44N/AN/ADetails
ScopolamineMuscarinic acetylcholine receptor M2Ki (nM)2N/AN/ADetails
ScopolamineMuscarinic acetylcholine receptor M3Ki (nM)0.44N/AN/ADetails
ScopolamineMuscarinic acetylcholine receptor M4Ki (nM)0.8N/AN/ADetails
TrihexyphenidylMuscarinic acetylcholine receptor M1Ki (nM)1.6N/AN/ADetails
TrihexyphenidylMuscarinic acetylcholine receptor M2Ki (nM)7N/AN/ADetails
TrihexyphenidylMuscarinic acetylcholine receptor M3Ki (nM)6.4N/AN/ADetails
TrihexyphenidylMuscarinic acetylcholine receptor M4Ki (nM)2.6N/AN/ADetails