C cc c

Cla Trana monoamine oxidase. Its clinical use is in the treatment of severe depression. The compound exists as two geometric isomers: cis and trans. Unlike dimethylcyclopropane, however, where reflection symmetry exist for each geometric isomer, here, because of the presence of two different substituents, each isomer is chiral and therefore resolvable into a pair of enantiomers. The trans pair is the stronger inhibitor and is marketed as the race-mate. The cis isomers exhibit much weaker enzyme inhibition. One possibility for this decreased effectiveness is a partial eclipsing of the two functions due to their proximity to each other.

It is important to differentiate the terms configuration and conformation. Configurations can best be thought of as set in their ways (i.e., stabler relationships of groups to each other in space). Cis-trans isomers fit into this category, especially as seen in the case of ali-cyclic rings such as the 1,2-dimethylcyclopropane and tranylcypromine. Interconversion of these isomers cannot occur without bond breaking. In conformations changes of relative spatial positions of substituents are almost totally unhindered because of free rotation around single bonds. Impedance, if any, is very small. Energy barriers are 1-2 kcal/mole. If the groups are bulky, the barriers are somewhat higher, making certain positions [i.e., conformers (or rotamers) somewhat more favored]. Such steric effects usually mean that favored conformations are those where such groups are at maximum distances from each other. This is called a staggered conformation. However, in cases where such functional groups may be subject to weak interactions such as hydrogen bonds, the stability patterns may shift. Because of the ease of conformer interchangeability, they are impossible to isolate. However, they are useful in conceptualizing drug interactions with receptors and other biopolymeric surfaces. An early idea that evolved was that only one conformer was likely to have the "best fit" to interact maximally with the receptor. This concept was subsequently superseded by the assumption that even in the case of a rigid receptor requirement, the binding drug molecule whose lowest energy (most stable) conformer might not have the best "goodness of fit" could easily change to more favorable conformations. Since energy barriers to such conformational changes are so low, the energies needed to effect the changes are available. They can even be released by the binding process itself. In addition, the probability that receptor and macromolecular surfaces are also flexible further minimized the requirement for a lowest-energy conformer for effective drug-receptor binding (see the later discussion of induced fit theory).

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