1-ARYLPIPERAZINES: CRYSTAL STRUCTURE VS. MODELS OF PHARMACOPHORE FOR AGONISTS AND ANTAGONISTS OF SEROTONIN 5-HT_lA RECEPTORS.

A.Fruziňski², M.Mokrosz¹, A.Bojarski^l, J.Karolak-Wojciechowska²

¹Institute of Pharmacalogy, Polish Academy of S'ciences, 31-343 Kraków, Poland
²lnstitute of General and Ecological Chemistry, Technical University, 90-924 Lódž, Poland

Hundreds of compounds belonging to the wide 1-arylpiperazine family are classified as potent 5-HTlA receptor ligands however, of different functional activity from agonists and partial agonists to antagonists. There is a well-known suggestion that the binding mode which discriminate between agonist and antagonist should come from different anchoring sites at the receptor, which means at the same, that the compounds should adopt distinct bioactive conformations.

There is a large collection of the 5-HT1A receptor agonists and partial agonists, while only three compounds can be regarded as full, pre- and postsynaptic 5-HT_1A receptor antagonists which limits the study. The real problem however, is the conformational flexibility of the majority of ligands which is brought in to the molecule by an aliphatic chain, usually linking 1- arylpiperazine with different terminal fragments.

The crystal structure refinement, a conformational analysis and structure- activity relationship studies there are tools which we apply to recognise the structural requirements suitable for the binding a ligand to the receptor and to find out what makes the molecules adopt and stabilised difFerent conformations at the receptor. Are we ready to answer this question right now?

This study was supported by Polish State Committee for Scientific Research (KBIV), grant no 4 P05F 01111