Pfeiffers rule

If the activity ratio is lower than 2 Eu/Rac 2 (e.g. Eu/ Rac = 2/1.6), we are in the presence of two active isomers. The distomer reinforces the activity of the eutomer. Such a situation indicates a decrease of the receptor selectivity. 

The activity ratio is Eu/Rac = 1 in this case both isomers are equipotent and no stereoselectivity is observed. This can be explained by the assumption (a) that the compounds act through a non-specific mechanism, (b) that the active compound and the receptor make only a two-point contact with the chiral center, (c) that the chiral center is not involved in the contact (is located in a silent region ). 

One usually admits that the discriminative effect between the two enantiomers increases with the proximity of the chiral center to the site of interaction with the receptor. An empirical rule published by Pfeiffer in 1956 states 

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Another example of the use of the MTD and MTD approaches can be found in a series of optically active o-phenoxypropionic acids with auxin-like activity, partly published in ( ). The R-stereo isomers are much more active than the S-analoges. Both series were analyzed by Lien et al. (10) and a correlation with ir, a and the Van der Waals volume was found. The Pfeiffer rule is explained in terms of different structural requirements for the substituents as measured by and van der Waals volume. Analysing the series using STERIMOL delivered equations containing too many parameters. In Table III the equations are given as a result of... 

Chirality, and the Cahn-Ingold-Prelog and Pfeiffer Rules... 

The coordinating groups must be arranged in the ligand structure so that they form a five-membered ring with the central ion (Pfeiffer s rule [173]). 

The introduction of asymmetry, followed by resolution, can be used to gain selectivity from a promiscuous molecule. Closely related receptors may differ only in the shape or size of their non-polar (hydrophobic) areas. Because of this, it makes sense to try to exploit differences in hydrophobic binding. Ariens (1986) exemplifies this by referring to derivatives of diphenhydramine (44, Ri = R2 = H). Table 3 is compiled from the data of Rekker et al. (1971) and shows how a 10-fold selectivity of diphenhydramine for the histamine receptor has been translated into an increase in potency and more than 100-fold selectivity towards the histamine receptor in the (-F)-methyl derivative, and to an increase in potency and more than 100-fold increase in selectivity towards the acetylcholine receptor in the (-)-r-butyl derivative. The data provide a good example of Pfeiffer s Rule (Pfeiffer, 1956) that enantiomeric potency ratios increase with potency. Many examples of this rule have been reviewed by Lehmann (1986). 

In this he had to oppose the strong tradition of van t Hoff and Wislicenus (1887), whose ideas of structure were sound, but whose notions about the stereochemical course of reactions were often erroneous. After a vigorous polemic with Wislicenus, Michael emerged victorious on the trans rule of stereoselection (Pfeiffer, 1904). 

The possibility that reacting species prefer to react along those paths in which they undergo the least modification has always been intuitively attractive. At one time or another, so-called principles of minimum structural change or deformation, configurational change, and minimum atomic and electronic motion have been invoked (Wheland, 1960 Hine, 1966). To account for Michael s rule of favored anti 1,2-addition, Pfeiffer formulated acetylenes as tram-heat structures in 1904 Frankland (1912) suggested that anti elimination is favored by an inherent tendency to centric symmetry. The more conscious applications of PLM by Muller after 1886, are probably misapplications of the principle, since they were usually concerned with complex pyrolytic reactions above 1000° (Muller and Peytral, 1924). 

Pfeiffer s rule States that in a series of chiral compounds the eudismic RATIO increases with increasing POTENCY of the EUTOMER. 

E. Pfeiffer s rule A. Isomer effects on absorption E. Deletion of the chiral center... 

Lien, E. J., Rodrigues de Miranda, J. E, Ariens, E. J. Quantitative structure-activity correlation of optical isomers a molecular basis for Pfeiffer s rule. Mol. Pharmacol. 1976, 12, 598-604. 

The three-point contact model Diastereoisomers Stereoselectivity ratios Pfeiffer s rule... 

Different QSAR equations have been derived for different enantiomers of phenoxypropionic acids [868], giving evidence for the validity of Pfeiffer s rule... 

Figure 47 Pfeiffer s rule [860], Eudismic indices (= logarithm of the ratio of the affinities of the more active analog to the less active analog) are plotted against the affinities pK, of the eutomers (open symbols, 1,3-oxathiolane 3-oxides 57, X = >SO filled symbols, 1,3-oxathiolanes 57, X = S circles indicate the affinities to the ileum muscarinic receptor, triangles indicate the affinities to the bladder receptor) (reproduced from Figure 2 of ref. [871] with permission from Elsevier Trends Journals, Cambridge, UK).

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