title: Geissoschizine methyl ether has third-generation antipsychotic-like actions at the dopamine and serotonin receptors.
abstract: Aripiprazole has made a significant contribution to the treatment of schizophrenia and related disorders. It has improved its safety and tolerability profiles, and these effects have been attributed to its pharmacological profile at the serotonin 5-HT and dopamine D(2) receptors. To discover compounds that have a similar pharmacological profile, we introduced a generic single-cell-based calcium imaging assay that standardizes the readouts from various assays used in previous studies on aripiprazole. In the present assay, the efficacy and potency of known ligands of serotonin 5-HT(1A), 5-HT(2A), 5-HT(2C), 5-HT(7) and dopamine D(2L) receptors were comparable to those found in previous studies using a variety of readouts. The developed assay was also able to reproduce the partial agonist activity, the low intrinsic activity and the selective activation of aripiprazole at the dopamine D(2L) receptors. Under identical experimental conditions, geissoschizine methyl ether (GM), a plant indole alkaloid, behaved as a partial agonist at the serotonin 5-HT(1A) receptor, a partial agonist/antagonist at the dopamine D(2L) receptor and an antagonist at the serotonin 5-HT(2A), 5-HT(2C) and 5-HT(7) receptors. Interestingly, GM showed a relatively low intrinsic activity and evoked a partial activation response in a subset of cells expressing the dopamine D(2L) receptor; both of these effects were similarly observed for aripiprazole. Although GM is far less potent at the dopamine receptor than aripiprazole at dopamine D(2L) receptors (EC(50)=4.4 μM for GM vs. EC(50)=56 nM for aripiprazole), GM and GM derivatives may comprise a new set of candidates for atypical antipsychotics.
authors.affiliation: Department of Neurobiology and Anatomy, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan. tueda@med.nagoya-cu.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueda
authors.forename: Shinya
authors.initials: S
authors.lastname: Ugawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ishida
authors.forename: Shoichi
authors.initials: S
authors.lastname: Shimada
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D026121:Indole Alkaloids; D007211:Indoles; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; C113776:dopamine D2L receptor; C110832:geissoschizine methylether