Stereochemistry

Receptors, enzymes, and other pharmacological targets, which by nature are composed of protein constructs, are highly chiral. Thus, it is not surprising that chirality in the drug structures normally plays an important role in pharmacological responses (Chapter 5). In racemic drug candidates, the

n ch3

n ch3

N"n s

FIGURE I.5 Arecoline and analogues.

desired pharmacological effect typically resides in one enantiomer, whereas the other stereoisomer(s) are pharmacologically inactive or possess different pharmacological effects. Thus, chiral drugs should preferentially be resolved into stereochemically pure isomers prior to pharmacological examination. Since many, especially of older date, synthetically prepared chiral biologically active compounds have been described pharmacologically as racemates, much of the pharmacological literature should be read and interpreted with great care.

Figure I.6 exemplifies the importance of stereochemistry in studies of the relationship between structure and pharmacological activity (SAR studies).

The upper part of Figure I.6 shows the four stereoisomers, which actually are two pairs of enantiomers of two diastereomeric compounds. These 1-piperazino-3-phenylindans were synthesized, resolved, structurally analyzed, and pharmacologically characterized as part of a comprehensive drug research program in the field of central biogenic amine neurotransmission. Whereas one of these stereoisomers turned out to be inactive, two of them were inhibitors of dopamine (DA) and noradrenaline (NE) uptake, and one isomer showed antagonist effects at DA, NE, and serotonin (5-HT) receptors. It is evident that a pharmacological characterization of a synthetic mixture of these compounds would be meaningless.

The 3-isoxazolol amino acid, APPA, is an analogue of the standard agonist, AMPA, for the AMPA subgroup of excitatory glutamate receptors (Chapter 15). APPA was tested pharmacologically as the racemate, which showed the characteristics of a partial agonist at AMPA receptors. Subsequent pharmacological characterization of the pure enantiomers quite surprisingly disclosed that (5)-APPA is a full AMPA receptor agonist, whereas (R)-APPA turned out to be an AMPA antagonist. This observation prompted intensive pharmacological studies, and as a result it was demonstrated that administration of a fixed ratio of an agonist and a competitive antagonist always provides a partial agonist response at an efficacy level dependent on the administered ratio of compounds and their relative potencies as agonist and antagonist. This phenomenon was named "functional partial agonism." An interesting aspect of this pharmacological concept is that administration of an antagonist drug inherently establishes functional partial agonism together with the endogenous agonist at the target receptor.

(1S, 3R)-Enantiomer (1R, 3R)-Enantiomer

I DA-/NE-uptake inhibitors |

(1S, 3S)-Enantiomer

(1S, 3S)-Enantiomer

Inactive

OH N

FIGURE 1.6 Chemical structures of the four stereoisomers of 1-piperazino-3-phenylindans and the two enantiomers of the phenyl analogue of AMPA (APPA).

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