Ionizable center

Equation (5) is of more academic than practical use, but demonstrates the critical role that the introduction of a molecular charge has on the lipophilicity of drugs and drug candidates, which often bear an ionization center and may thus be partially or completely ionized at physiological pH. 

The incorporation of an ionizable center, such as an amine or similar function, into a template can bring a number of benefits, including water solubility. A key step in the discovery of the protease inhibitor, indinavir was the incorporation of a basic amine (and a pyridine) into the backbone of hydroxyethylene transition state mimic compounds L-685,434 to enhance solubility (and potency) (Fig. 1.2) [17]. 

Molecules can have more than one pKa depending on the number of ionizable centers. In pharmaceutical research the ionization state between pH 2 (stomach) and 8 (pH in colon) is most interesting. A review by Taylor covers the effects of the different protonization/ionization forms of a molecule on pharmacokinetic and pharmacodynamic properties. Molecules are less soluble in aqueous media but more permeable through membranes in their neutral form. 

It is important to note that p/f determined in one of the above-mentioned experiments only provides information on a species with k protons bound, but says nothing about where exactly these protons are located. In fact, with n ionization centers... 

Limited to diprotic and perfectly symmetric systems only ( apparent exact constants in ACD terminology) Limited to 5 ionization centers per molecule only Estimates only principal acid and base pK ... 

Basic ionizable center (positively charged at physiological pH of about 7) (e.g., aliphatic amines, amidines/guanidines, and 4-amino pyridine)... 

The partition coefficient refers to the intrinsic lipophilicity of the drug, in the context of the equilibrium of unionized drug between the aqueous and organic phases. If the drug has more than one ionization center, the distribution of species present will depend on the pH. The concentration of the ionized drug in the aqueous phase will therefore have an effect on the overall observed partition coefficient. This leads to the definition of the distribution coefficient (log D) of a compound, which takes into account the dissociation of weak acids and bases. 

This type of detector enables the user to measure the number of X photons and also to know where the ionization center of the gas molecules is along the anode [CHA 70]. This makes it a one-dimensional (or two-dimensional) detector [GAB 78, SUL 94] that can measure the function 1 = f(x) (or I = f (x,y)), where x is the position. The position is determined by measuring the time difference for the signal to travel along the anode between the impact point and one of its ends. A multichannel analyzer memorizes the number of hits per channel. 

The pKa value provides a measure of the acid or basic properties of a compound. Specifically, the pKa value indicates the tendency of a molecule or ion to keep a proton (H+) at its ionization center(s). In terms of absorption, pA"., is an important criterion to help determine whether a molecule will be taken up by aqueous tissue components or lipid membranes (lipophilicity). 

Fig. 15. An interpretation of the middle three pH states of oxidized cytochrome c. Top State II, with both of the nonheme iron ligands displaced. Histidine-18 is ionized. Center State III, with methionine-80 and histidine-18 as ligands. Bottom High pH state IV, with methionine-80 replaced, probably by a deprotonated lysine-79.

In 1969 Yunusov and his co-workers (143) reported on their mass spectral studies of aconitine- and lycoctonine-type alkaloids. On the basis of mass spectral analysis of isotalatizidine (61), condelphine (67), talatizamine (68), neoline (47), aconitine (4), aconine, lycoctonine (58), and some of their derivatives, they reported that the main ionization center in these alkaloids is the nitrogen atom. During the study of lycoctonine-type alkaloids, they observed that the base peak is usually derived by the loss of the C-l substituents as a radical. If a C-3 substituent was present, as in many of the aconitine-type alkaloids, the heteroring fragmented in a... 

D. vulgaris and two ionizable centers in D. desulfuricans ATCC27774 that result in concerted two-electron/two-proton transfer steps has been called proton-thrusting, because it is akin to the redox-linked proton-transfer mechanisms seen in membrane-bound protein complexes involved in proton pumping. 

Consider now the charge distribution of ionized centers in the depletion region. For comparison, two cases can illustrate the difference between crystalline and a-Si H. The two cases are for n-type semiconductors, one with a single band of donor levels and the other with a uniform density of donor levels throughout the band gap. These two cases are illustrated in Fig. 2. In these cases, Poisson s equation can be explicitly solved. The solutions yield parabolic bands for the case with a single donor band and an exponential behavior for the continuous uniform-state density. The field dependences of the two cases differ also. For the discrete level, a linear dependence results, whereas an exponential behavior is obtained in the uniform-state case. The most striking difference is in the density of ionized states, which is uniform... 

This method measures the UV change induced by ionization instead of the volume of titrant necessary to change pH. Spectrophotometric titration is a powerful technique that works with relatively low concentrations of analyte (factor 10—Slower compared to potentiometric titration), thus preventing sample precipitation for a larger proportion of the samples. The interpretation of experimental data is relatively easy when one considers a single ionization. It becomes significantly more complex if the molecule has several ionizable centers, and even more if they overlap. In this case sophisticated numerical procedures like target factor analysis have to be used. ... 

At larger concentrations of ionized centers, R < x and the position of the barrier maximum remains halfway between centers, independent of F. The lowering of the barrier due to the field is then proportional to e RF/2 so that... 

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