STUDIES ON QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (QSAR) OF 3-METHYLFENTANYL DERIVATIVES

The correlation between physicochemical properties and analgesic activities of a series of 3-methylfentanyl derivatives was studied. Physicochemical parameters used in the multiple regression analysis were partition coefficient (log P), molecular weight (log MW) of compounds, hydrophobic parameters (π) of substituents R₁, R₂ and R₃, Verloop constants (L, B₁, B₂, B₃, B₄), molar refractivity. (MR) of R₂ and Hammett constants (σ) of R₃. The indicator variable I₀ was assigned the value of 1 for compounds containing OH group at the asterisked carbon, otherwise, 0. Correlation analysis was performed in five sub-sets and the results are as follows:1. No regular relationship between the analgesic activity and partition coefficients was found. The log P values in tables 1 and 2 showed that these compounds have higher lipid solubility. Thus, they could readily penetrate through blood-brain barrier and reach receptor sites. Their analgesic potency was mainly dependent on their specific receptor binding affinity.2. The best correlation in each sub-set is equations 8, 20, 32, and 36. Their squared correlation matrices between different parameters used in the most significant equations showed that there is some degree of intercorrelation except equations 8 and 12.3. σ² (equations 27～32) was found to be an important parameter (σ₀=0.04, T>2).4. Introducing a β-hydroxy group is beneficial to analgesic activity.5. According to the result of equation 32 a new compound 44 (fig 3) was designed and prepared, the observed log 1/c of which is very close to the calculated value.In summary, the bioactivity is closely dependent on the physicochemical properties of substituents R₂ and R₃: strict parameter requirements of hydrophobic constant, steric parameters for R₂ and Hammett constants for R₃. They are important groups interacting with receptor. R₃ may interact with receptor through Van der Waals-type forces and R₂ may bind to a hydrophobic cavity of certain size on the receptor surface, whereas substituent R₁ only play a carrier role in the drug transport process.