Abstract
Objectives: Acid-base dissociations constants of a series of poorly water-soluble nicotinic ligands designed as anti-inflammatory agents were determined in order to characterize the pharmacokinetic profile of this kind of ligands. Methods: pKas values were assessed by means of potentiometric and electrophoretic methods and investigated by computational protocols. Results: Both electrophoretic and potentiometric measurements produced reliable results. However, with the electrophoretic technique only an average value for close pKas was found, whereas the potentiometric method allowed determination of each pKa value in water-cosolvent mixtures. A theoretical treatment with various prediction programs - i.e. ADME Boxes v. 4.1, ACD/pKa DB and ACD/pKa GALAS - led in most cases to values which were not in accordance with the experimental ones. Conclusion: Electrophoretic and potentiometric techniques showed complementary features. Indeed, with capillary electrophoresis, the problem associated with the low water solubility of the studied samples could be easily overcome, although this technique did not allow to measuring all dissociation constants. In contrast, application of the potentiometric method afforded all the theoretical pKa values, although we had to perform the titrations in watercosolvent mixtures, a less precise, more laborious and time-consuming approach.
Highlights
The cholinergic anti-inflammatory pathway is a physiological mechanism modulating host inflammatory responses and immune system through cholinergic transmission mediated by α7 nicotinic acetylcholine receptors expressed on macrophages, human microvascular endothelial cells and other cytokine-producing cells [1,2]
We reported the measure of the acid-base dissociation constants for a set of nicotinic acetylcholine receptors (nAChRs) ligands with both potentiometric and electrophoretic methods [15]
Experimental pKa values measured by capillary electrophoresis fell in the same range of the theoretical values from the ACD/pKa Classic software and the ACD/ pKa GALAS software but not with those calculated by applying the ADME Boxes algorithm
Summary
The cholinergic anti-inflammatory pathway is a physiological mechanism modulating host inflammatory responses and immune system through cholinergic transmission mediated by α7 nicotinic acetylcholine receptors (nAChRs) expressed on macrophages, human microvascular endothelial cells and other cytokine-producing cells [1,2]. The α7 receptor subtype is placed at the apex of key CNS and peripheral cellular pathways that are involved in anti-inflammatory processes as well as cell survival Given these roles, selective activation of α7 nAChR is a viable and promising therapeutic strategy for a variety of disorders involving cognitive deficits and neurodegeneration and for inflammatory-related diseases and conditions [4,5]. As part of an ongoing research program on the study of novel heterocyclic derivatives targeting nAChR subtypes [7,8,9,10], we designed and prepared the set of compounds 2-9, in which the ∆2-isoxazoline moiety of reference ligand 1 was replaced by the 1,2,3-triazole ring (Figure 1) Along with their pharmacodynamic profile, ligands of putative pharmacological significance must be investigated for their physicochemical features such as solubility, lipophilicity, hydrogen bonding capacity and charge, which affect their in vivo pharmacokinetic behaviour. Biologically active derivatives are often fully or partially ionized at physiological pH and the presence of ionisable groups is often essential in directing their pharmacological response
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