Comparative molecular field analysis to derive pharmacophore maps for disposition parameters of intravenous anaesthetic agents

作者：Sear J W^*

来源：British Journal of Anaesthesia, 2012, 109(4): 595-602.

DOI：10.1093/bja/aes231

• anaesthetics i
• v
• cardiovascular depression
• comparative molecular field analysis
• disposition of i
• v
• anaesthetic agents
• model
• computer simulation

The present study examines the molecular basis of the disposition kinetics for i.v. hypnotic agents using comparative molecular field analysis (CoMFA).
The systemic clearance (Cl-s litre min(1)) and apparent volume of distribution at steady state (Vd(ss) litres) for 14 i.v. anaesthetics in human subjects were obtained from the literature, or from unpublished data, and used to form CoMFA models for the two aspects of drug disposition. Molecular alignment was achieved by field-fit minimization with the lead structure for all models eltanolone. The resulting pharmacophore maps were also compared with the pharmacophores for cardiovascular depression (expressed in terms of the drug concentration in 50 patients, associated with a 20 decrease in mean arterial pressure during infusion anaesthesia in the absence of other adjuvant drugs or noxious stimulation), which were taken from the literature.
The CoMFA model for Cl was based on two latent variables, explained 95.2 of the variance in observed activities, and showed good intrinsic predictability (cross-validated q(2) 0.663). The model for Vd(ss) was also based on two latent variables: r(2) 0.986 and q(2) 0.718. Comparison of the pharmacophores for the two disposition parameters showed poor correlation for both electrostatic and steric regions (r0.220 and 0.018; both NS). The relative contributions of electrostatic and steric interactions differed between the models (Cl-s 1.9:1; Vd(ss) 2.5:1). Comparison with the cardiovascular pharmacophores depression models gave r values of 0.551 (P0.05) and 0.407 (ns) for Cl-s (for electrostatic and steric models) and 0.225 and 0.448 for Vd(ss) (both ns).
Comparison of CoMFA models for drug disposition show only small elements of commonality, suggesting different molecular features may be responsible are two properties. There was better similarity for both disposition pharmacophores with the pharmacophores for cardiovascular depression.

• 出版日期2012-10