Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT2C Receptor

Obesity prevalence continues to be a foremost health concern across the globe leading to the development of major health risk conditions like type II diabetes, hyperlipidemia, hypertension and even cancers. Because of the deprived drug-based management system, there is an urgent need for the development of new drugs aiming at satiety and appetite control targets. Among the reported satiety signaling targets, 5HT2C receptor plays a crucial role in decreasing appetite and has become a promising target for the development of anti-obesity drugs. Lorcaserin, a 5HT2C receptor agonist and the only drug available in the market, was designed based on the receptor mechanism of action. Due to limited drug options available and considering the adverse drug effects of Lorcaserin, the development of new drugs which are highly specific toward the 5HT2C target and with lesser side effects is essential. The present study is majorly focused on developing new 5HT2C agonists through computational approaches like screening, docking, and simulation using Phase, QikProp, Glide and Desmond applications of the Schrodinger suite. Screening protocols resulted in eight best hit molecules with affinity for the receptor and among them, five hits displayed binding affinity toward the conserved residue Asp 134 of the receptor. The stability of the five molecules in complex with the 5HT2C receptor was studied through molecular dynamic simulations. Three molecules, ZINC32123870, ZINC40312983 and ZINC32124535, maintained stable interactions with the Asp 134 residue throughout the 50 ns simulation run time. Further, due to the high sequence similarity seen among the receptors of 5HT2 family, the three potential hits were cross validated against other subtypes 5HT2A and 5HT2B of the 5HT2 family to determine the specificity of the molecules against the target. Among the three hits, ZINC32124535 was identified as the best potential hit based on the hydrogen bond interaction percentage with Asp residue [5HT2A (Asp 155:60%); 5HT2B (Asp155: No interaction); 5HT2C (Asp 134:86%)]. The ZINC32124535 molecule produced one salt bridge and hydrogen bond interactions with Asp 134, alike the known drug Lorcaserin. Based on the results, ZINC32124535 was identified as the best potential hit against the 5HT2C receptor.

Agomelatine in unipolar depression in clinical practice: a retrospective chart review

Agomelatine (Valdoxan), a synthetic melatonergic receptor agonist at the MT1 and MT2 receptors, was first used in the management of sleep disorder. Its 5HT2C receptor antagonistic properties support its antidepressant potential. It is currently licensed in the UK, Europe and USA for the treatment of major depressive disorder. Although the randomized controlled evidence base for its use is growing, there are no retrospective, naturalistic studies available. We aimed to determine the tolerability and clinical effectiveness of agomelatine in unipolar depression. We also examined whether being refractory to treatment altered clinical outcome. Forty-eight patient records were examined. Twenty-five percent were treatment refractory: Clinical Global Impression (CGI) Severity score at the start of treatment was 3.81 compared with 3.38 at the end of treatment. Fifty-four percent improved at least minimally; only 12.5% were much or very much improved. Treatment-refractory patients had a poorer outcome with higher discontinuation rates and lower CGI Improvement ( p = 0.0205). Treatment-refractory patients also had a higher CGI Severity score at the end of treatment than at treatment commencement (3.92 versus 3.75), although this was not statistically significant.

an Investigation of 5-ht2 Involvement in the Acute Behavioural Effects of Fluoxetine and MCPP in an Animal Model of OCD

Background:We reported that the non-specific 5HT agonist m-chlorophenylpiperazine (mCPP) and the SSRI fluoxetine (FLX) both cause acute persistence increases in the rewarded alternation (RA) model of OCD. Chronic pretreatment with either substance or their combined subclinical doses protects from this ‘pathogenic’ effect, so mCPP and fluoxetine exhibit cross-tolerance and synergy.Aims:Using specific 5HT2A and 5HT2C receptor antagonists we investigated whether these receptors participate in a common mechanism of action mediating the acute mCPP/fluoxetine effect in our model.Methods:Naïve, male Wistars were used. Drugs used (intraperitoneally): FLX (10mg/kg), mCPP (2.5mg/kg), M100907 (5HT2A antagonist, 0.03mg/kg), SB242084 (5HT2C antagonist, 0.5mg/kg), vehicle. Experiments included a drug-free training/baseline phase in T-maze RA (group-matching for spontaneous persistence: SP).Experiment 1: Effects of M100907, SB242084, vehicle were assessed on 3 matched low SP and 3 high SP groups.Experiment 2: the acute effect of FLX, mCPP and saline were examined on RA in 3 SP-matched groups.Experiment 3: Effects of Vehicle+FLX, M100900+FLX, SB242084+FLX and Vehicle were examined on RA, in 4 SP-matched groups.Experiment 4: Correspondingly for mCPP.Results:Experiment 1: Neither M100907 nor SB242084 affected high or low SP.Experiment 2 replicated the pathogenic effects of FLX/mCPP.Experiment 3: Neither M100907 nor SB242084 affected the pathogenic effect of FLX.Experiment 4: in contrast, SB242084 (but not M100907) significantly reduced the pathogenic mCPP effect.Conclusions:The acute pathogenic action of mCPP, but not of FLX, involves 5HT2C but not 5HT2A receptors. the similar acute action of mCPP and FLX on persistence cannot be attributed to 5HT2 mediation.