Lipophilic functionality, absence

In our model, we have indicated that atypical antipsychotics (12) (sulpiride, metoclopramide, molindone, and Ro 22-1319) differ from classical neuroleptics (tricyclics, butyrophenones, butaclamol, diphenyl-piperidines) by lacking a lipophilic functional group on the basic nitrogen that could extend into the auxiliary binding site identified in our model. The absence of this lipophilic functionality may now be stated to be the characteristic which distinguishes selective D-2 dopamine receptor antagonists from non-selective antagonists. 

The partition coefficient (log P) describes the intrinsic lipophilicitY of the collection of functional groups and carbon skeleton, which combine to make up the structure of the compound, in the absence of dissociation or ionization. Methods to measure partition and distribution coefficients have been described [3,4]. 

More recently, the concept of the molecular lipophilicity potential (MLP), initially introduced by Audry and coworkers (2), has attracted increasing attention. The method involves mapping the local lipophilicity at points in 3D space around a chemical compound through the use of a parametrized fragmental system coupled to an empirical distance function. Despite the absence of any physical basis for the distance-dependent functions introduced, and the difficulties inher-... 

The solubilities of products and reagents must be considered, or problems can occur from formation of emulsions or unwanted precipitates that add extra steps and delay processing. The product may be extracted into a waste stream and not recovered. Solubilities can be obtained or anticipated from literature data and anticipated from parameters of hydrophihcity/lipophilicity and the presence or absence of ionizable functional groups. 

Figure 13.6 Relationship between lipophilicity (logD7.4) and CYP3A4 inhibition for 2 subpopulations of chemistry within the dataset identified by the presence (filled circles) or absence (open circles) of a sterically unhindered pyridine, imidazole, or triazole function. The broken lines are 95% confidence intervals. Reproduced with permission ref. 53.

Two more factors contributing to the persistence of xenobiotics in polychaetes, molluscs, crustaceans and echinoderms, and presumably other marine invertebrates, are the formation of macromolecular adducts and the slow release of free metabolites. The incorporation of PAH into more stable compartments , possibly as a result of cytochrome P-450-mediated adduct formation, is particularly evident in molluscs (see Fig. 3). The metabolites of many xenobiotics are lost more slowly than the parent compound, resulting in a build-up in the tissues during both exposure and subsequent depuration periods. The primary function of metabolism, therefore, appears to be detoxication, by preventing the formation of specific reactive metabolites and, probably more importantly, the non-specific toxic action of lipophilic xenobiotics caused by their penetration of membrane systems. Loss of metabolites down a concentration gradient occurs, reducing body burden of the xenobiotic, but is obviously limited by the absence or ineffectiveness of specific transport and excretory systems for the polar metabolites. 

Hyrophilicity and lipophilicity of polymer layers can be controlled by the presence or absence of functional groups - example is the existence of carboxylic acids in polymer structure. 

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