Potent antagonism of 5-HT₃ and 5-HT₆ receptors by olanzapine

Abstract

The interaction of the psychotropic agent olanzapine with serotonin 5-HT₃ and 5-HT₆ receptors was investigated. Olanzapine did not contract the isolated guinea pig ileum, but blocked contractions induced by the 5-HT₃ receptor agonist 2-methyl serotonin (2-CH₃ 5-HT) with a pK_B value of 6.38±0.03, close to the affinity of the 5-HT₃ receptor antagonist ondansetron. The atypical antipsychotic risperidone (1 μM) did not significantly inhibit 2-CH₃ 5-HT-induced contractions. Olanzapine had high affinity (pK_i=8.30±0.06) for human 5-HT₆ receptors in radioligand binding studies. Olanzapine did not stimulate [³⁵S]guanosine-5′-O-(3-thio)triphosphate ([³⁵S]GTPγS) binding to the G protein G_s in cells containing human 5-HT₆ receptors, but inhibited 5-HT-stimulated [³⁵S]GTPγS binding (pK_B=7.38±0.16). Among other antipsychotics investigated, clozapine antagonized 5-HT₆ receptors with a pK_B=7.42±0.15, ziprasidone was three-fold less potent, and risperidone, quetiapine and haloperidol were weak antagonists. Thus, olanzapine was not an agonist, but was a potent antagonist at 5-HT₆ receptors and had marked antagonism at 5-HT₃ receptors.

Introduction

Olanzapine is a psychotropic agent that has been shown to be therapeutically useful for the treatment of schizophrenia, bipolar disorder-associated mania, and the behavioral symptoms of Alzheimer's disease Beasley et al., 1996, Tohen et al., 1999, Tohen et al., 2000, Street et al., 2000. Olanzapine has relatively high affinity for many neuronal receptors including dopamine D₁–D₅, α₁-adrenoceptors, histamine H₁ receptors, 5-HT_2A, 5-HT_2B, 5-HT_2C, 5-HT₃ and 5-HT₆ receptors Bymaster et al., 1996, Bymaster et al., 1999c, Roth et al., 1994. Olanzapine also has moderate affinity for muscarinic M_1–5 receptors (Bymaster and Falcone, 2000). Olanzapine is an antagonist at dopamine D₁, D₂, and D₄ receptors Bymaster et al., 1999b, Gilliland and Alper, 2000, Newman-Tancredi et al., 1997, 5-HT₂-type receptors, muscarinic M₁–M₅ receptors, α₁-adrenoceptors, and histamine H₁ receptors (Bymaster et al., 1999b). The functional blockade of these multiple receptors may contribute to the wide range of pharmacologic and therapeutic activities of olanzapine, which have been described as multi-acting-receptor-targeted-agent (MARTA) (Bymaster et al., 1999a).

Although olanzapine possesses marked 5-HT₃ and 5-HT₆ affinity, its functional activity at these receptors has not been determined. Whether olanzapine acts as an agonist or antagonist at these receptors may impact the spectrum of olanzapine's potential therapeutic effects. The 5-HT₃ receptor is a ligand-gated ion channel and is found in smooth muscle including the small intestine and colon in the periphery and brain regions such as the hippocampus, striatum, and area postrema Morales et al., 1998, Miyake et al., 1995. Clinically, antagonists of the 5-HT₃ receptor are useful for treatment of chemotherapy-related nausea Slaby et al., 2000, Martin et al., 1998 and irritable bowel syndrome Farthing, 1999, Mertz, 1999. In addition, 5-HT₃ receptor antagonists are potentially useful for treatment of neuroleptic-resistant Tourette's syndrome (Toren et al., 1999), neuroleptic-induced tardive dyskinesia (Sirota et al., 2000), and fibromyalgia syndrome (Farber et al., 2000). Antagonists of 5-HT₃ receptors may also have a potential role in treatment of cognitive disorders and anxiety symptoms (Wolf, 2000) characterized by reduced release of central nervous system acetylcholine Ramirez et al., 1996, Wolf, 2000.

The 5-HT₆ receptors are coupled to the G protein G_s and stimulate adenylate cyclase activity. They are found in brain regions including the striatum, nucleus accumbens, cortex, and hippocampus Monsma et al., 1993, Kohen et al., 1996. Antagonism of the 5-HT₆ receptor has been suggested to produce antipsychotic, anxiolytic, and anticonvulsant properties, and particularly enhancement of cognitive performance (improved visual–spatial performance and enhanced consolidation of new learning) in animal models Bourson et al., 1998, Yoshioka et al., 1998, Routledge et al., 2000, Rogers et al., 1999, Meneses, 2001.

Because of the potential importance of these two receptors to the action of antipsychotic agents, it was of interest to characterize the interaction of olanzapine with these two receptors and to compare olanzapine to several typical and atypical antipsychotic agents. We explored the 5-HT₃ interactions of olanzapine using the guinea pig ileum in vitro, a model established to possess 5-HT₃ receptors (Cohen et al., 1989). The binding of a nonhydrolyzable analog of GTP, [³⁵S]guanosine-5′-O-(3-thio)triphosphate ([³⁵S]GTPγS), to the heterotrimeric GTP binding protein G_s using an antibody capture technique was used to determine the functional effects of olanzapine at clonal 5-HT₆ receptors.