Design of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists toward schizophrenia: An integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations.

The extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D2 and serotonin 5-HT2A receptors. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of D2 receptor (CoMFA-1, q2 = 0.767, r2 = 0.969; CoMSIA-1, q2 = 0.717, r2 = 0.978) and 5-HT2A receptor antagonists (CoMFA-2, q2 = 0.703, r2 = 0.946; CoMSIA-2, q2 = 0.675, r2 = 0.916) were successfully constructed using 35 tetrahydropyridopyrimidinone derivatives. Topomer CoMFA and HQSAR models were then constructed to further validate and supplement above models. Results showed that all models had good predictive power and stability. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking and molecular dynamic studies also suggested that the hydrogen bonding, electrostatic and hydrophobic interactions played key roles in the formation of stable binding sites. Meanwhile, several key residues like ASP114, TRP100, PHE389 of dopamine D2 receptor and ASP134, PHE328, TRP324 of serotonin 5-HT2A receptor were identified. Based on above findings, seven compounds were obtained through bioisostere replacement and ten compounds were designed by contour map analysis, in which the predicted activity of compounds S6 and DS2 were equivalent to that of the template compound 15. 3D-QSAR and ADMET predictions indicated that all newly designed compounds had great biological activity and physicochemical properties. Moreover, based on the best pharmacophore model, four compounds (Z1, Z2, Z3 and Z4) with new backbones were obtained by virtual screening. Overall, this study could provide theoretical guidance for the structural optimization, design and synthesis of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists. Abbreviations3D-QSARThree-dimensional quantitative structure-activity relationship5-HT2ARSerotonin 5-hydroxytryptamine 5-HT2A receptor5-HT2CRSerotonin 5-hydroxytryptamine 5-HT2C receptor receptorCADDComputer-aided drug designCoMFAComparative molecular field analysisCoMSIAComparative molecular similarity index analysisD2RDopamine D(2) receptorGPCRG-protein coupled receptorPLSPartial least squares regressionHQSARHologram quantitative structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Retrospective Demonstration of 25I-NBOMe Acute Poisoning Using Hair Analysis.

BACKGROUND: The abuse of new psychoactive substances or NPS has been dramatically increasing all around the world since the last half of the year 2000 and has become a serious public health problem. NPS are a challenge for the worldwide forensic community due to the difficulties to accurately document the cases. The N-benzylmethoxy (NBOMe) group is a new class of hallucinogenic designer drugs and has gained importance in recent years. 25I-NBOMe (2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)- methyl]ethanamine) is an analog of the 2C series of psychedelic phenethylamine drugs that contain an N-methoxybenzyl substituent, which significantly affects their pharmacological activities. It is a potent agonist of 5-HTA receptors and a severe hallucinogenic drug, with numerous irreversible psychedelic effects which can last from 5 to 10 hours. It is consumed most often in the form of drops or blotters by the transmucosal, sublingual or intranasal routes. The active dosage is very low, supposed to be less than 100 µg. The literature is poor in reporting cases where 25I-NBOMe was identified. Only very few clinical cases of over dosages were published, suggesting a low prevalence of this compound. METHODS: We present a retrospective demonstration of 25I-NBOMe acute poisoning with dramatic outcome, using hair analysis. Two hair strands, measuring 9.5 cm, were collected 6.5 months after drug consumption during a forensic clinical evaluation of brain dysfunctions after cardiorespiratory arrest and were analyzed by ultra-high performance liquid chromatography system coupled to a tandem mass spectrometry (UPLC-MS/MS) and using two specific transitions: m/z 428.1 > 121.2 (quantification) and 428.1 > 90.6 (confirmation). Hair strands were segmented to determine the historic pattern of drug use and differentiate a single exposure from a chronic exposure. The hair test result for 25I-NBOMe was the following: not detected (0-2 cm), not detected (2-4 cm), 1.0 pg/mg (4-6 cm), 4.9 pg/mg (6-8 cm) and not detected (8-9.5 cm). RESULT: The result of the segment 6-8 cm coincides with the date of consumption (calculated with a hair growth rate at 1 cm/month) and the low concentration detected in the segment 4-6 cm probably corresponds to the contribution of dormant hair. The toxicological significance of the measured concentrations is difficult to determine because this is the first case dealing with hair analysis for 25I-NBOMe. CONCLUSION: The use of hair analysis for NPS is still at the initial stages. In particular, little is known about the incorporation into the keratin matrix after intake and the correlation between dosage frequency of use, and hair concentrations. Under these circumstances, NPS hair analysis should be cautiously interpreted by experienced forensic toxicologist.