Medicinal chemistry I 22-1-2017

Partition Coefficient  partition-coefficient (P) or distribution-coefficient (D) is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium.  The most common physicochemical descriptor is the molecule’s partition coefficient in an octanol/water system. After administration a drug will go through a series of partitioning steps: (a) leaving the aqueous extracellular fluids. (b) passing through lipid membranes. (c) entering other aqueous environments before reaching the receptor. In this sense, a drug is undergoing the same partitioning phenomenon that happens to any chemical in a separatory funnel containing water and a nonpolar solvent such as hexane, chloroform, or ether.

The partition coefficient (P) is the ratio of the molar concentration of chemical in the non-aqueous phase (usually 1-octanol) versus that in the aqueous phase. The difference between the separatory funnel model and what actually occurs in the body is that the partitioning in the funnel will reach an equilibrium at which the rate of chemical leaving the aqueous phase and entering the organic phase will equal the rate of the chemical moving from the organic phase to the aqueous phase.

Refer to Figure in the next slide, and note that dynamic changes are occurring to the drug, such as it being metabolized, bound to serum albumin, excreted from the body, and bound to receptors. The environment for the drug is not static. Upon administration, the drug will be pushed through the membranes because of the high concentration of drug in the extracellular fluids relative to the concentration in the intracellular compartments. In an attempt to maintain equilibrium ratios, the flow of the drug will be from systemic circulation through the membranes onto the receptors. As the drug is metabolized and excreted from the body, it will be pulled back across the membranes, and the concentration of drug at the receptors will decrease.

Because much of the time the drug’s movement across membranes is a partitioning process, the partition coefficient has become the most common physicochemical property. The question that now must be asked is what immiscible nonpolar solvent system best mimics the water/lipid membrane barriers found in the body? The n-octanol/water system is an excellent estimator of drug partitioning in biological systems, why?

Cell membrane These membranes are not exclusively anhydrous fatty or oily structures, they can be considered bilayers composed of lipids consisting of a polar cap and large hydrophobic tail. Phosphoglycerides are major components of lipid bilayers. Other groups of bifunctional lipids include the sphingomyelins, galactocerebrosides, and plasmalogens.

The hydrophobic portion is composed largely of unsaturated fatty acids, mostly with cis double bonds. In addition, there are considerable amounts of cholesterol esters, protein, and charged mucopolysaccharides in the lipid membranes. The final result is that these membranes are highly organized structures composed of channels for transport of important molecules such as metabolites, chemical regulators (hormones), amino acids, glucose, and fatty acids into the cell and removal of waste products and biochemically produced products out of the cell.

For purposes of the partitioning phenomenon, picture the cellular membranes as two layers of lipids. The two outer layers, one facing the interior and the other facing the exterior of the cell, consist of the polar ends of the bifunctional lipids. Keep in mind that these surfaces are exposed to an aqueous polar environment. The polar ends of the charged phospholipids and other bifunctional lipids are solvated by the water molecules. There are also considerable amounts of charged proteins and mucopolysaccharides present on the surface. In contrast, the interior of the membrane is populated by the hydrophobic aliphatic chains from the fatty acid esters.

With this representation in mind, a partial explanation can be presented as to why the n-octanol/water partitioning system seems to mimic the lipid membranes/water systems found in the body. It turns out that n-octanol is not as nonpolar as initially might be predicted. Water-saturated octanol contains 2.3 M water because the small water molecule easily clusters around octanol’s hydroxy moiety. n-Octanol–saturated water contains little of the organic phase because of the large hydrophobic 8-carbon chain of octanol. The water in the n-octanol phase apparently approximates the polar properties of the lipid bilayer, whereas the lack of octanol in the water phase mimics the physiological aqueous compartments, which are relatively free of nonpolar components.

In contrast, partitioning systems such as hexane/water and chloroform/water contain so little water in the organic phase that they are poor models for the lipid bilayer/water system found in the body. At the same time, remember that the n-octanol/water system is only an approximation of the actual environment found in the interface between the cellular membranes and the extracellular/intracellular fluids.

Structure–Activity Relationships The structure–activity relationship (SAR) is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism. This allows modification of the effect or the potency of a bioactive compound (typically a drug) by changing its chemical structure.  Medicinal chemists use the techniques of chemical synthesis to insert new chemical groups into the biomedical compound and test the modifications for their biological effects.

Isosterism The concept of isosterism has evolved and changed significantly in the years since its introduction by Langmuir in 1919. Langmuir defined isosteres as compounds or groups of atoms having the same number and arrangement of electrons. Isosteres would possess similar physical properties and biological activities. For example, the molecules N2 and CO both possess 14 total electrons and no charge and show similar physical properties. Related examples described by Langmuir were CO2, N2O. N3 , and NCO. *(Table 2.11) your book .

With increased understanding of the structures of molecules, less emphasis has been placed on the number of electrons involved, because variations in hybridization during bond formation may lead to considerable differences in the angles, lengths, and polarities of bonds formed by atoms with the same number of peripheral electrons. Even the same atom may vary widely in its structural and electronic characteristics when it forms part of a different functional group. Thus, nitrogen is part of a planar structure in the nitro group but forms the apex of a pyramidal structure in ammonia and amines. Groups of atoms that impart similar physical or chemical properties to a molecule because of similarities in size, electronegativity, or stereochemistry are now frequently referred to by the general term of isostere.

Bioisostere In medicinal chemistry, bioisosteres are chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to another chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. Bioisosterism is used to reduce toxicity, change bioavailability, or modify the activity of the lead compound, and may alter the metabolism of the lead.

procainamide, an amide, has a longer duration of action than procaine, an ester, because of the isosteric replacement of the ester oxygen with a nitrogen atom.   Procainamide is a classical bioisostere because the valence electron structure of a disubstituted oxygen atom is the same as a trisubstituted nitrogen atom.

End