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Comparative Study
, 45 (11), 2352-4

Antagonism of the Five Cloned Human Muscarinic Cholinergic Receptors Expressed in CHO-K1 Cells by Antidepressants and Antihistaminics

Affiliations
Comparative Study

Antagonism of the Five Cloned Human Muscarinic Cholinergic Receptors Expressed in CHO-K1 Cells by Antidepressants and Antihistaminics

T Stanton et al. Biochem Pharmacol.

Abstract

Based on molecular cloning studies, five different muscarinic receptor subtypes exist: m1, m2, m3, m4, and m5. We determined the affinity and selectivity of binding for sixteen antidepressants, two of their metabolites, and three antihistaminics (H1) at these subtypes. Using Chinese hamster ovary cells (CHO-K1) transfected with genes for the human muscarinic receptor subtypes, we obtained equilibrium dissociation constants (Kds) from competitive radioligand binding studies with [3H]-quinuclidinyl benzilate ([3H]QNB) and membranal preparations of these cells. QNB was the most potent compound studied (Kd 30-80 pM). Mequitazine (Kd 6-14 nM) and amitriptyline (Kd 7-16 nM) exhibited the highest affinity among the antihistaminics and antidepressants, respectively. Among the antidepressants examined were the serotonin-selective drugs sertraline and fluoxetine, both of which displayed Kd values > 1 microM. The remaining antidepressants were moderate to weak antagonists with some eliciting no radioligand competition at high concentrations. The compounds studied showed no significant selectivity among the five cloned subtypes.

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