IV hypnotic drugs have several distinct therapeutic effects. We have used CoMFA to identify the molecular bases of induction of anesthesia; immobilization; and cardiovascular depression, together with those features associated with high systemic clearance and large volume of distribution. 14 structurally diverse agents have been used in all studies. Molecular alignment has been achieved by field-fit minimization, with a common lead structure for all models (5-beta-pregnanolone). Pharmacophore maps have been constructed to show both electrostatic and steric regions contributing to the models; and isocontours constructed linking those lattice points making the greatest 40% contributions to each model. Comparison of the different pharmacophores shows only small elements of commonality; suggesting that different molecular features may be responsible for both the beneficial properties of the hypnotic agents, with different molecular bases for cardiovascular depression, and for drug disposition and clearance.  Similar models have also been developed for the immobilizing properties of halogenated and non-halogenated voilatile anesthetic agents.

What do we know about the molecular features of anesthetic ligands?

243rd National Meeting (2012)

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