title: The novel trisubstituted pyran derivative D-142 has triple monoamine reuptake inhibitory activity and exerts potent antidepressant-like activity in rodents.
abstract: Major depression disorder is a significant health problem with 10-20% of all adults suffering from this disease. The underlying causes of depression are still unclear and 15% of depressed patients are resistant to all known therapies. Monoamine therapies have so far been the most successful approach for treating depression. Triple monoamine reuptake inhibitors have recently been implicated in generation of potent antidepressant activity while possibly exhibiting a low side-effect profile in addition to treating anhedonia. The additional, previously under-appreciated involvement of dopaminergic systems in depression prompted our efforts to develop novel asymmetric trisubstituted and disubstituted pyran derivatives as triple reuptake inhibitors. One of the lead compounds, D-142, exhibited uptake inhibition (K(i)) values of 29.3 nM, 14.7 nM and 59.3 ± 13.7 nM for norepinephrine, serotonin and dopamine transporters, respectively. Its affinity for serotonin transporter was comparable to fluoxetine, a well known SSRI. In the rat forced swimming test, compound D-142 exhibited potent antidepressant activity in the dose range tested (2.5, 5 and 10mg/kg) and was far more efficacious than the reference compound imipramine. In the mouse tail suspension test, compound D-142 reduced immobility in a dose (2.5, 5 and 10mg/kg) dependent manner, indicating a potent antidepressant effect. In locomotor activity tests, compound D-142 did not exhibit any stimulation in the same dose ranges. In the extended CNS receptors screening assay this molecule exhibited little or no non-specific interaction in the CNS, indicating high specificity for monoamine transporters. These results advance D-142 as a potential potent antidepressant.
authors.affiliation: Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI 48202, USA. adutta@wayne.edu
authors.forename: Aloke K
authors.initials: AK
authors.lastname: Dutta
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Gopishetty
authors.forename: Sanjib
authors.initials: S
authors.lastname: Gogoi
authors.forename: Solav
authors.initials: S
authors.lastname: Ali
authors.forename: Juan
authors.initials: J
authors.lastname: Zhen
authors.forename: Maarten
authors.initials: M
authors.lastname: Reith
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D055808:Drug Discovery; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013550:Swimming; D027981:Symporters / Q000037:antagonists & inhibitors
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; C570328:D-142 compound; D014179:Neurotransmitter Uptake Inhibitors; D011714:Pyrans; D027981:Symporters