Lipophilic fragments

The obvious drawback of this method is that the parent solute, at least, has to be available or must be synthesized, and its log P value has to be determined experimentally. Nys and Rekker therefore developed a method known as the fragmental constant approach, which is based on the additivity of fragment contributions to the molecular lipophilidty [7] (see Eq. (9), where a( is the inddence of fragment i, fi the lipophilic fragment constant, Ci a corredion factor, and the frequency of Cm). 

Anandamide was isolated from water-insoluble fractions of the porcine brain. It binds to CB1 with rather moderate affinity (Ki 61 nM) and a low affinity for the CB2 receptor (Ki 1930 nM). The name anandamide is based on its chemical nature (an amide) and the Sanskrit word ananda meaning bliss. The chemical structure of anandamide can be divided into two major molecular fragments a polar ethanolamido head group and a hydrophobic arachidonyl chain. The polar head group comprises a secondary amide functionality with an N-hydroxyalkyl substituent while the lipophilic fragment is a non-conjugated c/ s tetraolefinic chain and an n-pentyl chain reminiscent of the lipophilic side chain found in the classical cannabinoids. A number of anandamide analogs have been synthesized and demonstrated to have considerable selectivity for the CB1 receptor in comparison to the CB2 receptor. 

Figure 18 Two examples of micelles formed from the dynamics of amphiphile interactions. The dark faces represent the polar exterior of the molecules, and the light faces represent the lipophilic fragments of the amphiphiles.

Substituents in aromatic rings may influence each other in a number of ways depending on their chemical nature, mutual position, and the presence of other substituents. For example, methyl groups have relatively little electronic interaaion with an aromatic ring and with each other. Their incremental contribution to the lipophilicity of, say xylenes, is additive as expected, and independent from their relative position (ortho vs. meta vs. para). Such groups are thus well behaved in lipophilic fragmental systems. - ... 

In sharp contrast to a molecular electrostatic potential, the MLP is not obtained by calculating the interactions between a probe and the molecule. Rather, all interactions with the molecular environment are implicitly contained in the lipophilic fragmental values. What differentiates the various MLP methods in the literature is the use of different fragmental systems and different distance functions. All MLP methods do well in describing qualitatively the variations of lipophilicity in space, but until recently little attention was paid to the quantitative aspects of the MLP, used as criteria for comparing fragmental systems and distance functions, and as a tool for calculating log P values. 

K, V N Viswanadhan and J J Wendoloski 1998. Prediction of Hydrophobic (Lipophilic) lerties of Small Organic Molecules Using Fragmental Methods An Analysis of ALOGP and GP Methods. Journal of Physical Chemistry 102 3762-3772. 

Rekker, R. F., Mannhold, R. Calculation of Drug Lipophilicity. The Hydrophobic Fragmental Constant Approach, VCH, Weinheim, 1992. 

Mannhold, R., Rekker, R. F., Dross, K., Bijloo, G., De Vries, G. The lipophilic behaviour of organic compounds 1. An updating of the hydrophobic fragmental... 

Ghose, A. K., Viswanadhan, V. N., Wendoloski,).). Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods an analysis of... 

The application of Eq. (6) to predict lipophilicity for compounds with several functional groups runs into problems. The difficulties are associated with intramolecular interactions, which could not be addressed by addihve schemes as used in the SLIPPER model. Therefore, the authors correct the logP prediction of a given molecule according to the lipophilicity values of the nearest neighbors by using cosine similarity measures and molecular fragments [13, 14]. 

Residue analytical chemistry has extended its scope in recent decades from the simple analysis of chlorinated, lipophilic, nonpolar, persistent insecticides - analyzed in the first Si02 fraction after the all-destroying sulfuric acid cleanup by a gas chro-matography/electron capture detection (GC/ECD) method that was sometimes too sensitive to provide linearity beyond the required final concentration - to the monitoring of polar, even ionic, hydrophilic pesticides with structures giving the chemist no useful feature other than the molecule itself, hopefully to be ionized and fragmented for MS or MS" detection. 

In the former method, a molecule is decomposed into fragments, and the partition coefficient of this molecule is the sum of the lipophilicity increments fj of all the fragments ... 

Fig. 7. Estimates of the logarithm of partition coefficient in octanol water (log P) of 4-PIOL analog substituents obtained by use of Crippen s fragmentation method. Correlation between affinity tpAT,) and lipophilicity (log P) of the substituents of the 4-PIOL analogs. The two gray lines connect the high-affinity compounds (open squares) and the low-affinity compounds (open triangles), respectively, and the black line shows the correlation between the remaining compounds (black circles).

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