Quantitative Structure-activity Relationships Study (QSAR) Of Sigma (σ) Receptor Imaging Agents

Sigma (σ) receptors widely distribute over central nervous system (CNS), endocrine system, immune system, as well as the tumors. Sigma (σ) receptors have been proposed to be involved in cellular functions, biological processes and CNS neuropsychiatric diseases. Radiotracers with high affinity and selectivity forσ1 receptor may serve as the sensitive molecular probes for diagnosis of neuropsychiatric disorders. Radiotracers with high affinity and selectivity forσ2 receptor may used as tumor imaging agents. The application of Computer Aided-Drug Design (CADD) may greatly decrease the cost of novel drug research and development and accelerate the rate of drug design and development.In this thesis, CADD was applied to investigate the 3D-QSAR models ofσreceptor ligands and the interaction mechanism betweenσreceptors and their ligands. The results may be useful to design novel radiotracers with high affinity and high subtype selectivity forσ1 orσ2 receptors. The detailed studies are as follows.1. 3D-QSAR study of spiropiperidineσ1 receptor ligandsComparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models of 42 protonized and unprotonized spiropiperidine derivatives with different conformations were performed. 8 models were obtained with high predictive abilities. A series of 18F and 123I labeled spiropiperidine derivatives were designed asσ1 receptor rediotracers. Their affinities forσ1 receptor were predicted based on the obtained models. Competitive binding assays indicated that pKi values of 4 newly synthesized compounds were in good agreement with the predicted values, which demonstrated that these models were reliable. The results were useful in designing novel molecular probes with high affinity and selectivity forσ1 receptor.2. 3D-QSAR study of piperazineσ1 receptor ligandsComparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been employed on 3D-QSAR study of 27 piperazineσ1 receptor ligands. Quantitative structure-activity relationships was discussed based on the obtained CoMFA and CoMSIA models.3. 3D-QSAR study of azabicycloσ1 andσ2 receptor liandsAzabicyclo compounds showed affinities both forσ1 andσ2 receptors. CoMFA and CoMSIA studies were performed for 35 azabicycloσ1 receptor ligands and for 38 azabicycloσ2 receptor ligands. The differences between 3D-QSAR model ofσ1 receptors ligands and that ofσ2 receptors ligands were compared. The influences of different substitutes on the affinity forσ1 andσ2 receptors were discussed. The results were useful in designing novelσ1 andσ2 receptor ligands.4. Pharmacophore analysis ofσ1 andσ2 receptor ligandsDISCO was used for pharmacophore analysis of 9 different backbone molecules with high affinity forσ1 receptor and 5 different backbone molecules with high affinity forσ2 receptor. The pharmacophores ofσ1 receptor ligands andσ2 receptor ligands were derived, respectively. The above two pharmacophores were compared and the differences between them were discussed. The results would guide the further molecular design of newσ1 andσ2 receptor imaging agents with high subtype selectivity.