Receptor reserve-dependent properties of antipsychotics at human dopamine D2 receptors.

Abstract

Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist approved for use in the treatment of psychiatric disorders including schizophrenia, bipolar disorder, and unipolar depression in the US. Aripiprazole has demonstrated a relatively favorable side effect profile compared to other commonly prescribed antipsychotics, including a low propensity for treatment-limiting extrapyramidal symptoms, hyperprolactinemia, and body weight gain. In an effort to elucidate aripiprazole's pharmacological activity in relation to clinically relevant fluctuation of dopamine D(2) receptor reserves, we compared the properties of aripiprazole to other antipsychotics, quetiapine, clozapine, olanzapine, ziprasidone, risperidone and haloperidol, a dopamine D(2) receptor partial agonist, bifeprunox, dopamine D(3) receptor modulators, BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide), and a 5-HT(1A) partial agonist, buspirone using forskolin-stimulated cAMP accumulation in clonal Chinese hamster ovary cell lines expressing low and high densities of human dopamine D(2S) receptors (hD(2S)-Low and hD(2S)-High, respectively). In hD(2S)-Low cells lacking receptor reserves for dopamine, all drugs antagonized dopamine responses, and their potencies correlated well with respective affinities. In hD(2S)-High cells possessing receptor reserves, all antipsychotics except aripiprazole antagonized dopamine responses, and their antagonist potencies were less than those in hD(2S)-Low cells treated with the equal dopamine concentration. In contrast, aripiprazole and bifeprunox acted as full agonists. BP897, GR103691 and buspirone acted as partial agonists. These data suggest that the level of receptor reserves influences antagonist potencies and side effects associated with antipsychotics. Aripiprazole's unique receptor reserve dependent properties may account for its favorable tolerability in the clinical setting.

• Authors: Yoshihiro Tadori, Robert A Forbes, Robert D McQuade, Tetsuro Kikuchi
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 607 Issue 1-3 Pg. 35-40 (Apr 01 2009) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19217900 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Dopamine Agonists
• Piperazines
• Quinolones
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• Aripiprazole
• Dopamine

Topics

• Animals
• Antipsychotic Agents (administration & dosage, adverse effects, pharmacology)
• Aripiprazole
• CHO Cells
• Cricetinae
• Cricetulus
• Dopamine (administration & dosage)
• Dopamine Agonists (administration & dosage, adverse effects, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Piperazines (administration & dosage, adverse effects, pharmacology)
• Quinolones (administration & dosage, adverse effects, pharmacology)
• Receptors, Dopamine D2 (drug effects, metabolism)
• Receptors, Dopamine D3 (agonists)