Factors that influence tadpole narcosis. An LFER analysis

Abstract

Application of the new solvation equation to the results of Overton on tadpole narcosis yield the correlation given by eqn. (a), where C_nar is the narcotic concentration of solute in mol dm^–3 and the log (1/C_nar)= 0.579 + 0.824R₂– 0.334π₂^H– 2.871Σβ₂^o+ 3.097V_x(a) descriptors are R₂ the solute excess molar refraction, π₂^H the solute dipolarity/polarizability, Σβ₂^o the solute hydrogen-bond basicity and V_x the solute volume. For 84 solutes, the correlation coefficient, ρ, is 0.9730 and the standard deviation, sd, is 0.246 log units. The above equation shows that the two main factors that influence tadpole narcosis are solute hydrogen-bond basicity that decreases toxicity and solute volume that increases toxicity. Solute hydrogen-bond acidity has no effect at all.

The use of water–octanol partition coefficients as log P(oct) leads to the regression equation [eqn. (b)] log (1/C_nar)= 1.129 + 0.833log P(oct)(b) where ρ= 0.9212 and sd = 0.407 for the same 84 solutes. This equation is not improved by addition of [log P(oct)]² as a descriptor, but it is if V_x is included [eqn. (c)]. Now ρ= 0.9400 and sd = 0.359 log (1/C_nar)= 0.621 + 0.743log P(oct)+ 0.668V_x(c) log units. When additional data are added to the Overton set, similar equations to the above are obtained for 114 varied solutes, showing that tadpole narcosis is a general phenomenon.

Results on the narcosis of α,ω-diols and cycloalkanols can be interpreted using the analysis of Franks and Lieb. It is suggested that the anaesthetic binding site on the primary protein target is a large or flexible pocket, extending inward from the external water-facing surface, that is rather aqueous and of limited hydrophobicity.