RATIONALE: (-)-Stepholidine is a tetrahydroberberine alkaloid that is known to interact with dopamine receptors and has also been proposed as a novel antipsychotic agent. Its suggested novelty lies in the fact that it has been proposed to have D1-like receptor agonist and D2-like receptor antagonist properties. Thus, it might be effective in treating both positive and negative (cognition) symptoms of schizophrenia. However, its activity on specific dopamine receptor subtypes has not been clarified, especially with respect to its ability to activate D1-like receptors. OBJECTIVES: We wished to examine the affinity and functional activity of (-)-stepholidine at each of the human dopamine receptor subtypes expressed in a defined cellular environment. METHODS: D1-D5 dopamine receptors were stably expressed in cell lines and their interactions with (-)-stepholidine were examined using radioligand binding and various functional signaling assays. Radioligand binding assays were also performed using bovine striatal membranes. RESULTS: (-)-Stepholidine exhibited high (nM) affinity for D1 and D5 receptors, somewhat lower (two- to four-fold) affinity for D2 and D3 receptors, and low micromolar affinity for D4 receptors. Functionally, (-)-stepholidine was ineffective in activating G protein-mediated signaling of D1-like and D2 receptors and was also ineffective in stimulating β-arrestin recruitment to any dopamine receptor subtype. It did, however, antagonize all of these responses. It also antagonized D1-D2 heteromer-mediated Ca(2+) mobilization. Radioligand binding assays of D1-like receptors in brain membranes also indicated that (-)-stepholidine binds to the D1 receptor with antagonist-like properties. CONCLUSIONS: (-)-Stepholidine is a pan-dopamine receptor antagonist and its in vivo effects are largely mediated through dopamine receptor blockade with potential cross-talk to other receptors or signaling proteins.
RATIONALE: (-)-Stepholidine is a tetrahydroberberine alkaloid that is known to interact with dopamine receptors and has also been proposed as a novel antipsychotic agent. Its suggested novelty lies in the fact that it has been proposed to have D1-like receptor agonist and D2-like receptor antagonist properties. Thus, it might be effective in treating both positive and negative (cognition) symptoms of schizophrenia. However, its activity on specific dopamine receptor subtypes has not been clarified, especially with respect to its ability to activate D1-like receptors. OBJECTIVES: We wished to examine the affinity and functional activity of (-)-stepholidine at each of the humandopamine receptor subtypes expressed in a defined cellular environment. METHODS: D1-D5 dopamine receptors were stably expressed in cell lines and their interactions with (-)-stepholidine were examined using radioligand binding and various functional signaling assays. Radioligand binding assays were also performed using bovine striatal membranes. RESULTS:(-)-Stepholidine exhibited high (nM) affinity for D1 and D5 receptors, somewhat lower (two- to four-fold) affinity for D2 and D3 receptors, and low micromolar affinity for D4 receptors. Functionally, (-)-stepholidine was ineffective in activating G protein-mediated signaling of D1-like and D2 receptors and was also ineffective in stimulating β-arrestin recruitment to any dopamine receptor subtype. It did, however, antagonize all of these responses. It also antagonized D1-D2 heteromer-mediated Ca(2+) mobilization. Radioligand binding assays of D1-like receptors in brain membranes also indicated that (-)-stepholidine binds to the D1 receptor with antagonist-like properties. CONCLUSIONS:(-)-Stepholidine is a pan-dopamine receptor antagonist and its in vivo effects are largely mediated through dopamine receptor blockade with potential cross-talk to other receptors or signaling proteins.
Authors: Lin Pei; Shupeng Li; Min Wang; Mustansir Diwan; Hymie Anisman; Paul J Fletcher; José N Nobrega; Fang Liu Journal: Nat Med Date: 2010-11-28 Impact factor: 53.440
Authors: Nikhil M Urs; Joshua C Snyder; Jacob P R Jacobsen; Sean M Peterson; Marc G Caron Journal: Proc Natl Acad Sci U S A Date: 2012-11-27 Impact factor: 11.205
Authors: Vivek Kumar; Amy E Moritz; Thomas M Keck; Alessandro Bonifazi; Michael P Ellenberger; Christopher D Sibley; R Benjamin Free; Lei Shi; J Robert Lane; David R Sibley; Amy Hauck Newman Journal: J Med Chem Date: 2017-02-10 Impact factor: 7.446
Authors: Callum Hicks; Peng Huang; Linnet Ramos; Sunil U Nayak; Yohanka Caro; Allen B Reitz; Garry R Smith; David Y-W Lee; Scott M Rawls; Lee-Yuan Liu-Chen Journal: ACS Chem Neurosci Date: 2018-04-06 Impact factor: 4.418
Authors: Lani S Chun; Rakesh H Vekariya; R Benjamin Free; Yun Li; Da-Ting Lin; Ping Su; Fang Liu; Yoon Namkung; Stephane A Laporte; Amy E Moritz; Jeffrey Aubé; Kevin J Frankowski; David R Sibley Journal: Front Synaptic Neurosci Date: 2018-02-21
Authors: Thomas M Keck; R Benjamin Free; Marilyn M Day; Sonvia L Brown; Michele S Maddaluna; Griffin Fountain; Charles Cooper; Brooke Fallon; Matthew Holmes; Christopher T Stang; Russell Burkhardt; Alessandro Bonifazi; Michael P Ellenberger; Amy H Newman; David R Sibley; Chun Wu; Comfort A Boateng Journal: J Med Chem Date: 2019-04-01 Impact factor: 8.039
Authors: Rajat Kumar Pal; Satishkumar Gadhiya; Steven Ramsey; Pierpaolo Cordone; Lauren Wickstrom; Wayne W Harding; Tom Kurtzman; Emilio Gallicchio Journal: PLoS One Date: 2019-09-30 Impact factor: 3.240