Pfeiffer s rule

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). 

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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