title: Further structure-activity relationship studies on 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: identification of compounds with triple uptake inhibitory activity as potential antidepressant agents.
abstract: To investigate structural alterations of the lead triple uptake inhibitor molecule, disubstituted 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol, we have carried out structure-activity relationship (SAR) studies to investigate the effect of alteration of aromatic substitutions and introduction of heterocyclic aromatic moieties on this molecular template. The novel compounds were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. SAR results indicate dopamine norepinephrine reuptake inhibitory (DNRI) type activity in thiophene (10g) and pyrrole (10i) derivatives. On the other hand, 3-hydroxyphenyl derivative 10f and 4-methoxyphenyl derivative 10j exhibited a triple reuptake inhibitory (TUI) activity profile, as these molecules exhibited potent uptake inhibition for all the monoamine transporters (K(i) of 31.3, 40, 38.5 and K(i) of 15.9, 12.9, 29.3 for DAT, SERT, and NET for 10f and 10g, respectively). Compound 10f was further evaluated in the rat forced swim test to evaluate its potential antidepressant effect. The results show significant reduction of immobility by TUI 10f at 10 mg/kg dose, indicating potential antidepressant activity.
authors: Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, United States.
authors: Bhaskar
authors: B
authors: Gopishetty
authors: Stuart
authors: S
authors: Hazeldine
authors: Soumava
authors: S
authors: Santra
authors: Mark
authors: M
authors: Johnson
authors: Gyan
authors: G
authors: Modi
authors: Solav
authors: S
authors: Ali
authors: Juan
authors: J
authors: Zhen
authors: Maarten
authors: M
authors: Reith
authors: Aloke
authors: A
authors: Dutta
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011714:Pyrans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D014179:Neurotransmitter Uptake Inhibitors; D011714:Pyrans