The Ionization of Phenolic Amines, Including Apomorphine, Dopamine and Catecholamines and an Assessment of Zwitterion Constants

Abstract

I The dissociation constants of many phenolic amines, including benzylamines, phenethylamines, phenylethanolamines, phenylpropylamines, catecholamines, and apomorphine have been measured by potentiometric titration at 25°C. Measurements have also been made with many of their methoxy derivatives and with series of phenolic quaternary ammonium salts. Some compounds were also studied at 370C. 2 Usually at least five titrations were made with each compound and Debye-Huckel theory was applied to convert concentrations to activities but the estimates of pKa were not constant and found to increase with increasing concentration. The range studied was usually 5-15 mM and a least-squares line-fit, based on the empirical assumption that pK5 varies with (concentration)"12, has been used to calculate values for 10 mm solutions and to extrapolate to infinite dilution and to 100 mM. The dependence of pKa on concentration was much less at 370C than at 25°C. 3 At 370C the pKa values of many biologically interesting compounds in the group, dopamine, noradrenaline, adrenaline and isoprenaline, coryneine (the trimethylammonium derivative of dopamine) and apomorphine are within 1 log unit of physiological pH, indicating the presence of a significant proportion of either the zwitterion or of the uncharged phenolic amine. 4 Zwitterion constants have been estimated from the pKa values of the phenolic amines and those of their methoxy and quaternary trimethylammonium analogues. Zwitterion formation does not appear to be associated with activity at a-adrenoceptors and probably not with activity at P-receptors. The active species seems likely to.contain the unionised phenolic group but at dopamine receptors this may be in the uncharged phenolic amine rather than in the phenolic ammonium salt.

THE EFFECTS OF pH ON THE AFFINITY OF PIRENZEPINE FOR MUSCARINIC RECEPTORS IN THE GUINEA‐PIG ILEUM AND RAT FUNDUS STRIP

“…This was determined electrometrically with a Metrohm Model E 500 pH meter, as in previous work (Armstrong & Barlow, 1976: Barlow & Burston, 1979. The calculations incorporate activity coefficients based on the ionic strength and should estimate the thermodynamic pKa.…”

Effect of urinary pH and flow rate on catecholamine excretion.

“…Lewis' (1954) measurements were made at 20°C and values at 370C are slightly higher (Armstrong & Barlow, 1976). Two factors further complicate the pH effect on the activity of amines.…”

The Ionization of Morphine, Hydroxy Amphetamine and (+)‐tubocurarine Chloride and a New Method for Calculating Zwitterion Constants

“…The activity coefficient was calculated from the ionic strength using Debye-Huckel parameters (Armstrong & Barlow, 1976). The ionization constants, K1 and K2, were calculated from pairs of experimental values of C, A, [H+] and [OH-] by the method of Britton (1942; see Albert & Sergeant, 1962) and, as in previous work, the pairs consisted of results arranged on either side of the half-neutralization point.…”

“…Electrometric titrations ofsalts ofphenolic amines These were made as described by Armstrong & Barlow (1976) but with the more accurate digital pH meter (Metrohm E 500) used by Barlow & Burston (1980). Weighed amounts of the salts were dissolved in water or 0.1 M NaCl and the pH was measured after the addition of accurately measured volumes of 0.1 M NaOH.…”

“…The extent of zwitterion formation will depend upon the ease with which a proton leaves the phenolic group rather than the amino group and measurements of the pK. of phenolic quaternary ammonium salts have shown that the presence of a positive charge on a nearby nitrogen atom greatly enhances the ionization of a phenolic group (Armstrong & Barlow, 1976; Barlow & Burston, 1980).…”