The Size of Hydroxyl Groups in Solution and the Changes in Size Associated With the Ionization of Phenolic, Carboxylic and Amino Groups in Phenolic Quaternary Ammonium Salts, Nicotine and Some Amino Acids: Possible Implications for Drug‐water and Drug‐receptor Interactions

Abstract

I Size in solution can be expressed either as the apparent molal volume at infinite dilution (0') and the concentration parameter (j) or as the partial molal volume of the solute at infinite dilution (V°) and the concentration parameter for the solute or solvent (q, or q%). Although calculated differently, these are derived from the same results and are equivalent.2 From measurements with phenolic quatemary ammonium salts, including compounds with high nicotine-like activity, the apparent size of the hydroxyl group in water is small and variable. Phenolic groups are slightly larger than alcoholic groups, which should be better hydrogen donors. 3 By measuring the volume change associated with ionisation it is possible to measure the size of charged groups such as phenate and carboxylate; these are much smaller than phenolic and carboxyl. Ammonium groups, however, are only slightly smaller than the corresponding amines. 4 The zwitterion forms of amino acids are associated with a minimum in volume but the volume changes increase with chain length from glycine to y-aminobutyric acid. Groups separated by less than this distance interact in their effects on water. 5 Decreases in volume or unexpectedly small increments in apparent molal volume represent decreases in entropy which must be taken into account in drug-water-receptor interactions. Although they may be offset by enthalpy changes, they should favour binding because there is more scope for an increase in entropy. This might explain the association of the small apparent size in water of the hydroxyl group in many compounds with its effects on their affinity for receptors.

AFFINITIES OF THE PROTONATED AND NON‐PROTONATED FORMS OF HYOSCINE AND HYOSCINE N‐OXIDE FOR MUSCARINIC RECEPTORS OF THE GUINEA‐PIG ILEUM AND A COMPARISON OF THEIR SIZE IN SOLUTION WITH THAT OF ATROPINE

“…will appear bigger. With hyoscine the fraction is about 0.1% but with hyoscine N-oxide HBr it is between 1 and 2 % in these experi- tion) as in previous work (Barlow, 1980). The effect cm3/mol (Barlow, 1980 The results show that coulombic forces do not make a very big contribution to the binding of hyoscine to .muscarine-sensitive acetylcholine receptors in the guinea-pig ileum.…”

“…With hyoscine the fraction is about 0.1% but with hyoscine N-oxide HBr it is between 1 and 2 % in these experi- tion) as in previous work (Barlow, 1980). The effect cm3/mol (Barlow, 1980 The results show that coulombic forces do not make a very big contribution to the binding of hyoscine to .muscarine-sensitive acetylcholine receptors in the guinea-pig ileum. This is consistent with the calculations made by Burgen (1965) and with the comparisons between compounds containing quaternary nitrogen and quaternary carbon made by Barlow & Tubby (1974).…”

“…It has been suggested that the decrease in entropy associated with the reduction in volume such as is seen with compounds containing hydroxyl groups could lead to increased binding to receptors if this process involves the breakup of these drug-water interactions (Barlow, 1980). The high affinity of both ionized and unionized forms of hyoscine might therefore be partly due to such an effect; hyoscine may bind better than hyoscyamine because there is a bigger increase in entropy on adsorption.…”

“…Densities were determined with an Anton Paar Precision Density Meter 02D, calibrated with solutions of sodium chloride, exactly as in previous work (Lowe, MacGilp & Pritchard, 1973;Barlow & Franks, 1973;Barlow, 1980). The calculations of apparent molal volume (0j and of the volume change following the addition of alkali (AV) were made as described by Barlow (1980):…”

“…The calculations of apparent molal volume (0j and of the volume change following the addition of alkali (AV) were made as described by Barlow (1980):…”