Quantitative structure-retention relationships in the examination of the topography of the binding site of antihistamine drugs on α1-acid glycoprotein

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

“…For the two series of local anesthetics, the linear alkyl amino homologs of lidocaine and the piperidine ring-containing homologs of mepivacaine, we found a linear relationship (r 2 ϭ 0.82) between ⌬G (dissociation) for AGP binding and the octanol:buffer partition coefficient of the neutral drug species. The strong correlation between hydrophobicity and the affinity for the LAs is in accord with studies showing that generalized hydrophobicity is a major determinant of binding for other drug classes, including basic drugs such as antihistamines and antihypertensives (Kaliszan et al, 1996), diazepines (Maruyama et al, 1992), and phenothiazines (Miyoshi et al, 1992), as well as acidic drugs such as coumarin anticoagulants (Maruyama et al, 1990). That the same linear correlation holds for both homologous series, each with a different conformation of carbons around the amino nitrogen, implies that this hydrophobic interaction is relatively forgiving, suggesting that the binding site is a broad hydrophobic surface or a flexible pocket that can accommodate ligands with a range of sizes.…”

“…Although values for bupivacaine and lidocaine were previously reported Kaliszan et al, 1996;Cogswell et al, 2001), we repeated these determinations using our current lot of AGP and buffer system to allow valid comparison with the present determinations of the other compounds. Not only can the buffer affect the K D (Ravis et al, 1988), complicating comparisons of drug affinities under different conditions, but the composition and quality of commercial AGP are also known to vary significantly, even from lot to lot from the same supplier (Lunde et al, 1986;Morin et al, 1986;Hervé et al, 1997).…”

“…Ionic contributions were examined both by repeating the binding analyses with lidocaine at a higher pH (8.40), where the majority of the local anesthetic is unprotonated (pK a ϭ 8.19 at 25°C; Strichartz et al, 1990), and by using the permanently positively charged lidocaine analog QX-314. We contrast our results for the representative LAs examined here with the prevailing pharmacophoric model developed using a series of structurally related antihistamines (Kaliszan et al, 1996).…”

Enantioselective Retention of 4‐Aryl‐1,4‐dihydropyridine Calcium‐Channel Blockers on Human Serum Albumin and α 1 ‐Acid Glycoprotein HPLC Columns: Relationships with Different Scales of Lipophilicity

“…In fact, we found that the log P lipophilicity scale was not collinear with log k IAM w , mainly due to the particular behavior of the two basic DHPs. We also observed that biological phenomena that include interactions with biomembranes correlated better with log k IAM w than with log P. Moreover, Kaliszan and co-workers [11] [12] found that the interactions of 16 antihistamines and 7 b-blockers on an AGP phase were better related to log k IAM w than to log P. These observations suggest that the amphipatic nature of phospholipids allows them to be a more effective partition phase than octan-1-ol for describing partitioning in biomembranes as well as in other biological components such as proteins.…”

“…This is clearly the case for HSA [3 ± 9], whereas for AGP there was some dispute as to whether chromatographic data correlate with biochemical binding data [10] [11]. However, recent evidence confirms that AGP columns can yield retention data that correlate with protein binding data [11] [12]. The HPLC methods have the advantage of producing quantitatively comparable binding-related retention data for large sets of compounds.…”