CHIRALITY IN DRUG DISCOVERY RESEARCH. Uli Hacksell, Preclinical R&D, Astra Draco AB, S-221 00 Lund, Sweden.

Regulatory requirements regarding documentation of chiral drugs have been increased during recent years. Today, a new drug application of a chiral drug normally contains pharmacodynamic, pharmacokinetic and toxicological documentation on the individual enantiomers even if it is the racemate that is considered for therapeutic use. This additional documentation is time consuming and increases the cost for drug development. It might, therefore, be advantageous to aim for the development of achiral drugs. However, in drug discovery research, chiral drugs may offer certain advantages; provided that enantiopure compounds are studied, chiral molecules will provide much more information about receptor/enzyme - ligand/substrate interactions than achiral analogues. In addition, recently developed synthetic methods affording enantiopure compounds and analytical methods for quantifying enantiopurity are available. Several examples will be given demonstrating that enantiopure ligands have provided essential information on the molecular basis for activation of G-protein coupled receptors. It is of particular interest that the chirality of a receptor ligand may be used to fine-tune the pharmacological profile.