Eudismic ratios

To summarize the data in table 1, neither MDMA nor MBDB has hallu-cinogen-like discriminative stimulus properties. Symmetrical transfer of the MDMA and MBDB stimulus indicates that their primary discriminative stimulus effects are very similar. For both MDMA and MBDB, there is enantioselectivity for the S isomer, with about a twofold eudismic ratio. Finally, the substitution of (- )-amphetamine and cocaine in MDMA-trained rats may indicate that MDMA has some psychostimulant-like properties, while hffiDB seems to lack this activity. 

It is common to call the most active enantiomer eutomer and the less active one distomer. The ratio of the pharmacological activity of these are called the eudismic ratio (ER) and Pfeiffer s mle states that the lower the effective dose of a drug the greater the difference in the pharmacological effect of the optical isomers . When two enantiometic... 

The more active isomer (where activity refers to binding affinity at a defined receptor) is designated the eutomer, the less active is the distomer. The ratio of activities is the eudismic ratio, and its logarithm, the eudismic index, is then proportional to the difference in binding free energy between the enantiomers. The eudismic index is a quantitative measure of chiral discrimination. 

Activities (PA2) and eudismic ratios of optical isomers for diphenhydramine derivatives... 

It is important to introduce two other terms that compare the pharmacological activity of a pair of enantiomers. The isomer imparting the desired activity is called the eu-tomer (in the case of Thalidomide this is the R-enantiomer), whereas the isomer which is inactive or causes unwanted side effects is called the distomer (this is the S-enantiomer for Thalidomide). Comparison of the potencies of the two isomers comes from the eudismic ratio and this can be used in vitro or in vivo. 

CF3CH20 An example of a lack of stereoselectivity of pharmacological action. The enantiomers of flecainide demonstrates an eudismic ratio... 

The (+)-cis isomer of (108) was the most potent muscarinic of the series. It demonstrated a eudismic ratio of the same high order of magnitude as that for muscarine and the dioxolanes. This (+)-cis enantiomer has the same absolute configuration as the muscarini-cally most active L-(+)-muscarine (2) and the (+)-cis-dioxolane (109). The other isomers represented by structure (108), although much less potent than the (+)-cis isomer, also demonstrated a degree of muscarinic agonist effect. All four isomers of structure (108) showed similar nicotinic potency and activity, close to that of carbamyl choline, and eudismic ratios were small. 

Compound (110) is exponentially less potent than (11 l)at muscarinic receptors. Both compounds demonstrate low nicotinic potency and activity. The sulfone congeners (112) of the enantiomers (212,5JR and 2S,5S) of the cis-structure are weak muscarinics with a eudismic ratios of unity. 

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

Shortening of the aminopropyl to an aminoethyl chain in the eutomers of the HHD-deriva-tives (3->8, 4->9, 6- ll) did not change significantly the affinities. In contrast, the stereoselectivity ratios for the enantiomers of these aminopropyl/aminoethyl pairs were changed. It was found, that the stereoselectivity ratios for 3 (aminopropyl series) were higher than those for the related compound in the aminoethyl series (8). Vice versa, the amide of the HHD type (6) exhibited lower eudismic ratios than the amide of the THP type (11). 

The eudismic ratio (ER) is the antilog of the difference between the pAf and pD, values of the eutomers and the corresponding distomers. pD, values are the negative logarithm of the agonist concentration required to obtain 50% of the maximal stimulation of [ SjGTPyS. 

Similarly to the trend observed at aj -adrenoreceptors, stereoisomers (-)-31, (-l-)-31, (-)-32 and ( + )-32 displayed a radioreceptor binding affinity higher than that observed in functional assays at 5-HT, receptors. Furthermore, the eudismic ratio between (-)-31 and ( + )-31 enantiomers was identical to that observed in functional assays whereas for (- )-32 and (-I- )-32 it was much lower. However, a difference in potency observed for the agonists... 

Stereoselectivity was defined by Rauws ° as follows Stereoselectivity is the extent to which an enzyme or other macromolecule, or tnacromolecular structure (antibody or receptor) exhibits affinity towards one molecule of a pair of isomers in comparison with and in contrast to the other isomer. Lehmann has expressed this in a mathematical form the ratio of activity of the better fitting enantiomer (eutomer, Greek, eu = good), to that of the less fitting enantiomer (distomer Greek, dys = ba(i) is defined eudismic ratio. From this a eudismic affinity quotient can be derived (Table 17.3). 

One usually admits that the discriminative effect between the two enantiomers increases with the proximity of the chiral centre to the site of interaction with the receptor. An empirical rule published by Pfeiffer in 1956 states that the isomeric activity ratio (eudismic ratio) of a highly active... 

A summary of these data on monoamine uptake inhibition and on inhibition of binding by rat brain synaptosomes of the selective 5-HT uptake inhibitor paroxetine and the selective NE uptake inhibitor tomoxetine taken from [53] is shown in table 5. Although the eudismic ratio (potency less active isomer/potency active isomer) of the R and S isomers of fluoxetine is fairly dose to one i.e. 1.58, the selectivity index (antilog (pl 5-HT - Pkj NE) of the S isomer is much larger than that of the R isomer. In offier words the R isomer of fluoxetine is a less selective 5-HT uptake inhibitor than the S isomer but their potendes are similar. This is also confirmed by the data on the inhibition of H-paroxetine and H-tomoxetine binding. 

The eudismic ratio of the R- and S isomer for the inhibition of %-paroxetine is one, so their potencies are the same. However, the selectivity index for the inhibition of H-paroxetine and %[-tomoxetine binding is 24 for the R isomer and 155 for the S isomer of fluoxetine indicating that the R isomer is less selective than the S isomer in regard to the afflnily of the compounds for the 5-HT tremsporter versus the NE transporter. 

The activity of the racemic trans ( ) compound in vitro as well as in vivo is caused by McN 5652-Z its trans (+) enantiomer as the trans (-) enantiomer is comparatively inactive. The eudismic ratio for 5-HT uptake inhibition (Kj trans (-) / K trans (+)) is 150 and for NE uptake inhibition 155. The selectivity index of the trans (+) isomer for 5-HT upteike inhibition versus NE uptake inhibition (K NE / Kj 5-HT) is a moderate 4.6. 

Receptor Tissue Eutomer pA2 (enantiomer) Eudismic ratio... 

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