Fp. Bymaster et al., Antagonism by olanzapine of dopamine D1, serotonin(2), muscarinic, histamine H-1 and alpha(1),-adrenergic receptors in vitro, SCHIZOPHR R, 37(1), 1999, pp. 107-122
The atypical antipsychotic olanzapine has relatively high affinity for a nu
mber of neuronal receptors in radioreceptor binding assays. The ability of
olanzapine to activate or antagonize a number of neuronal receptors was inv
estigated in vitro, in cell lines transfected selectively with receptor sub
types and in receptor-selective isolated tissue studies. Olanzapine had no
agonist activity at any of the receptors examined. However, olanzapine was
a potent antagonist of 5-HT-stimulated increases in IP3 in cell lines trans
fected with 5-HT2A or 5-HT2B receptors with IC50 values of 30-40 nM. Olanza
pine weakly blocked 5-HT-induced formation of IP3 in cell lines transfected
with 5-HT2C receptors, but in this cell line potently inhibited 5-HT-stimu
lated [S-35]GTP gamma S binding with a K-i value of 15 nM. Olanzapine block
ed dopamine-stimulated adenylyl cyclase in rat retina with modest potency (
K-i=69 nM), consistent with its relatively low affinity for dopamine D1 rec
eptors. Olanzapine blocked agonist-induced activities at the muscarinic rec
eptor subtypes M-1, M-2, M-3, and M-5 with K-i values of 70, 622, 126, and
82 nM, respectively. In studies using cell lines transfected with muscarini
c M-4 receptors, olanzapine and the atypical antipsychotic clozapine did no
t have agonist activities as determined with cAMP inhibition and stimulatio
n assays, arachidonic acid release and [S-35]GTP gamma S binding assays. Ho
wever, olanzapine antagonized agonist-induced effects in muscarinic Mg cell
s with a Ki value of 350 nM. In isolated tissue studies, olanzapine potentl
y blocked agonist-induced effects at alpha(1)-adrenergic and histamine H-1
receptors (K-B=9 and 19 nM, respectively). Thus, olanzapine was an antagoni
st at all receptors investigated and was a particularly potent antagonist a
t 5-HT2A, 5-HT2B, 5-HT2C, alpha(1)-adrenergic and histamine H-1 receptors.
Olanzapine was a weaker antagonist at muscarinic and dopamine D1 receptors.
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