QSAR And Action Mechanism Studies Of 1-Phenylcyclohexylamine-like Drugs

1-Phenylcyclohexylamines(PCA) are a special kind of psychoactive drugs with lower toxicity, higher potent anticonvulsant activity. The studies of quantitative structure-activity relationship(QSAR) and action mechanism of the PCA-like drugs are very important for classification, designing, development and activity predicting of new drugs. This paper aims to build the QSAR models of these drugs according to the result of statistical analysis about the various descriptors, and to speculate the action mechanism of the drug with its receptor.The main works and conclusions are as follows:1. At first, the structures of seven PCA isomers were optimized and their frequencies were calculated using DFT/B3LYP method at the level of 6-31G with Gaussian 03 program, and then their single-point energies were calculated at the level of DFT/B3LYP/6-311+G(d,p). According to the results of frequencies and energies of each isomers, we discussed their relative stability and pointed out the dominant conformation of PCA.2. The single-point energies of 8 PCA enantiomers were calculated, and the results showed that each pair of enantiomers had the same physical and chemical properties(E,EHOMO,EHOMO-1,ELUMO,ELUMO+1,μ,H) in addition to the indicator variable(IRS). Form the analysis of their molecular orbitals and the charge distribution it could be indicated that the orbital interaction of all the PCA enantiomers with their receptor was very similar, and the electronic-transfer occurred mainly in the phenyl. The phenyl either could provide electron as a donor or accept electron from NH2 or phenyl as a receptor.3. To find out the relationship between the activity and molecular descriptors of PCA enantiomers, the multiple linear regression (MLR) analysis was carried out by taking the TI,TD50 and ED50 activity as the dependent variables respectively and the selected molecular descriptors as the independent variables. The obtained QSAR models were showed below: QSAR模型NRsFRcv2(1) TI= 98.346+254.316 Q6 8 0.904 0.412 26.943 0.6814(2) TD50=1041.115+308.12Q1+2460.541Ed 8 0.956 8.685 26.232 0.7147(3) ED50= 194.282+101.527Q1+7617.553ELUMO 8 0.968 2.117 37.641 0.7672From above QSAR models it could be showed that Q6 was the main factor affecting TI activity of these enantiomers and the cyclohexyl in meta-position was related to action point of drugs.4. We calculated the descriptors of 36 PCA-like drugs and got the corresponding QSAR model: TI=5.08+3.599Q1-5.981Q2-5.834Q4-1.808Q12+3.135Qc-0.305Es+0.192Eb-35.152ELUMO+1-0.409H N=33, R=0.931,s=0.350, F=16.552, Rcv2=0.7466From above QSAR model it can be showed that net charge, vibrational energy, orbital energy and hydrophobic were the main factor affecting TI activity of these drugs.5. According to the results of QSAR model of PCA-like drugs, a novel Conformation Complementary Judgement, Transformation and Induction (CCJTI) model was proposed to explain different action mechanism of PCA-like drugs with their target receptors. Based on the result of QSAR study and the CCJTI model, we classified the PCA-like drugs into electrostatic-interaction drug.6. We proposed a new designing method of drug, and it was named as Electronic Push-pulling method. Using the method, we had designed a new drug with higher predicting activity.