DOV-102677

Background:  Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol‐maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol‐preferring (P) rats.Methods:  Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed‐ratio 4 (FR4) schedule, DOV (1.56 to 50 mg/kg; PO) was given 25 minutes or 24 hours prior to evaluation. The effects of DOV (12.5 to 50 mg/kg; PO) in the FST were evaluated 25 minutes posttreatment.Results:  DOV (6.25 to 50 mg/kg) dose‐dependently reduced alcohol‐maintained responding by 59 to 88% at 25 minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50 mg/kg) was sustained for up to 120 hours after a single dose. Administration of a single dose of DOV (25, 50 mg/kg) 24 hours before testing suppressed alcohol responding for 48 hours by 59 to 62%. DOV (12.5 to 50 mg/kg) also dose‐dependently reduced immobility of P rats in the FST.Conclusions:  DOV produces both prolonged and selective reductions of alcohol‐motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD‐like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans.

Dysfunction of serotoninergic neurotransmission is known to be involved in the pathophysiology of major depression. The molecules that enhance the level of serotonin either via blocking serotonin reuptake or through inhibition of its metabolism are effective antidepressants. With this as the basis, a group of new molecules that supposedly effect serotoninergic neurotransmission were designed and tested. The new molecular entities (NME-2, NME-5, NME-16 and NME- 24) are active in animal models of behavioral despair. In the present study, the binding of these new NMEs to the serotonin transporter protein (SERT) has been modeled and their activity correlated with the behavioral pattern observed in the mouse forced swim test (FST) model. The putative binding orientations of the NMEs have been identified by docking the molecules into the active site of the SERT. A 3D model of the SERT active site was constructed using comparative protein modeling principles with the X-ray structure of the leucine transporter (LeuT) as template. 3D-QSAR models based on the CoRIA formalism were generated from the experimental data and docking scores for eight novel SERT inhibitors. The CoRIA models highlight the salient features for effective binding of NMEs to the serotonin transporter and are also able to predict pKd values. Based on the significant correlation between the anti-immobility effect seen in the mouse FST study and the binding energies obtained from the docking study along with insights from the interaction patterns with the receptor obtained from the docking, the CoRIA models can be used to suggest structural modifications that can help in optimization of the SERT inhibition. Experimental evidence shows that the NMEs are highly efficacious and could be developed into potential antidepressants.