Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics.
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.
Stanton
T
T
Department of Psychiatry, Mayo Foundation, Jacksonville, FL 32224.
Bolden-Watson
C
C
Cusack
B
B
Richelson
E
E
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D018727:Muscarinic Antagonists
D000928:Antidepressive Agents; D006634:Histamine H1 Antagonists; D018727:Muscarinic Antagonists