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

• Published in: British journal of anaesthesia : BJA Vol. 109; no. 4; pp. 595 - 602
• Main Author: Sear, J.W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-10-2012; Oxford University Press
• Subjects: anaesthetics i.v; Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthetics, Intravenous - chemistry; Anesthetics, Intravenous - pharmacokinetics; Anesthetics, Intravenous - pharmacology; Biological and medical sciences; cardiovascular depression; comparative molecular field analysis; Computer Simulation; Depression, Chemical; disposition of i.v. anaesthetic agents; Electrochemistry; Hemodynamics - drug effects; Hemodynamics - physiology; Humans; Least-Squares Analysis; Medical sciences; model, computer simulation; Models, Molecular; Models, Statistical; Molecular Conformation; Quantum Theory; Structure-Activity Relationship; cardiovascular depression; anaesthetics i.v; disposition of i.v. anaesthetic agents; model, computer simulation; comparative molecular field analysis; Mood disorder; Intravenous administration; Computer simulation; Anesthesia; Depression; anaesthetic agents; model; disposition of i.v
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aes231

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 (Cls litre min−1) and apparent volume of distribution at steady state (Vdss litres) for 14 i.v. anaesthetics in human subjects were obtained from the literature, or from unpublished data, and used to form CoMFA models for the two aspects of drug disposition.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 q2 0.663). The model for Vdss was also based on two latent variables: r2 0.986 and q2 0.718. Comparison of the pharmacophores for the two disposition parameters showed poor correlation for both electrostatic and steric regions (r=−0.220 and 0.018; both NS). The relative contributions of electrostatic and steric interactions differed between the models (Cls 1.9:1; Vdss 2.5:1). Comparison with the cardiovascular pharmacophores depression models gave r values of 0.551 (P<0.05) and 0.407 (ns) for Cls (for electrostatic and steric models) and −0.225 and −0.448 for Vdss (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.