Hydrolytic Stability of New Amino Acids Analogues of Memantine

In the present work, the hydrolytic stability of new memantine analogues modified with amino acids, at different pH corresponding to the human biological liquids and organs, was evaluated. Memantine is an uncompetitive N-methyl-d-aspartate receptor antagonist with low-to moderate-affinity. In addition, it is the first representative of a novel class of Alzheimer’s disease (AD) medications acting on the glutamatergic system by blocking N-methyl-D-aspartate receptors. Generally, prodrugs are compounds aiming to improve stability of active fragment and to facilitate transportation across the cell membranes or lipid barriers. The investigated series of prodrugs include modified memantine with the following amino acids: alanine, β-alanine, glycine, phenylalanine, and valine. Hydrolytic stability was determined at two different pH values 2.0 and 7.4 at 37 °C, similar to those in the human stomach and blood plasma. Specially developed UV-VIS spectrophotometric method for quantification of the concentrations of unchanged compounds was applied in the kinetic studies. Val-MEM is the most stable in neutral medium and at 37 °C compound with t1/2 = 50.2 h. The compound Phe-MEM has also very good hydrolytic stability with t1/2 = 29.6 h. The order of other compounds is: Val-MEM ≫ Phe-MEM ≫ Ala-MEM ≈ Val-MEM > β-Ala-MEM. Ala-MEM and Gly-MEM are the most stable compounds at acid condition with almost identical values for t1/2 = 17.8 h and t1/2 = 16.3 h, respectively. The stability of tested compounds in acid conditions are relatively less than in neutral one. They are ordered as follows: Ala-MEM ≈ Gly-MEM > Val-MEM ≈ Phe-MEM ≈ β-Ala-MEM. All compounds have relatively good hydrolytic stability of more than 10 h at both neutral and acid conditions, which is quite enough in order to pass in the blood circulation and to be used as a potential antimicrobial agent.

Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects

Despite a long history in medical and dental application, the molecular mechanism and precise site of action are still arguable for local anesthetics. Their effects are considered to be induced by acting on functional proteins, on membrane lipids, or on both. Local anesthetics primarily interact with sodium channels embedded in cell membranes to reduce the excitability of nerve cells and cardiomyocytes or produce a malfunction of the cardiovascular system. However, the membrane protein-interacting theory cannot explain all of the pharmacological and toxicological features of local anesthetics. The administered drug molecules must diffuse through the lipid barriers of nerve sheaths and penetrate into or across the lipid bilayers of cell membranes to reach the acting site on transmembrane proteins. Amphiphilic local anesthetics interact hydrophobically and electrostatically with lipid bilayers and modify their physicochemical property, with the direct inhibition of membrane functions, and with the resultant alteration of the membrane lipid environments surrounding transmembrane proteins and the subsequent protein conformational change, leading to the inhibition of channel functions. We review recent studies on the interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol. Understanding the membrane interactivity of local anesthetics would provide novel insights into their anesthetic and cardiotoxic effects.

The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist

Reviews of signal transduction have often focused on the cascades of protein kinases and protein phosphatases and their cytoplasmic substrates that become activated in response to extracellular signals. Lipids, lipid kinases, and lipid phosphatases have not received the same amount of attention as proteins in studies of signal transduction. However, lipids serve a variety of roles in signal transduction. They act as ligands that activate signal transduction pathways as well as mediators of signaling pathways, and lipids are the substrates of lipid kinases and lipid phosphatases. Cell membranes are the source of the lipids involved in signal transduction, but membranes also constitute lipid barriers that must be traversed by signal transduction pathways. The purpose of this review is to explore the magnitude and diversity of the roles of the cell membrane and lipids in signal transduction and to highlight the interrelatedness of families of lipid mediators in signal transduction.