Conformationally constrained butyrophenones as new pharmacological tools to study 5-HT2A and 5-HT2C receptor behaviours

This study presents new pharmacological and molecular modelling studies on a recently described series of conformationally constrained butyrophenones. Alignment-free three-dimensional quantitative structure-activity relationship models developed on the basis of GRid Independent descriptors and partial least squares regression analysis, allow feasible predictions of activity of new compounds and reveal structural requirements for optimal affinity, particularly in the case of the 5-HT2A receptor. The requirements for the 5-HT(2A)affinity consist in a precise distance between hydrogen bond donor (protonated amino group) and hydrogen bond acceptor groups, as well as an optimal distance between the protonated amino group and the farthest extreme of the compounds. Another significant result has been the characterisation of two structurally similar compounds as interesting pharmacological tools (1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine and 1-[(4-Oxo-4,5,6,7-teti-aliydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine). In spite of their structural similarity, the first compound shows clearly higher affinity for the 5-HT2C receptor (about 100 fold) and higher Meltzer ratio (1.17 vs. 0.99) than the second. Moreover, the first compound inhibits arachidonic acid release in a biphasic, concentration-dependent way in functional experiments at the 5-HT2C receptor and it acts as inverse agonist at the 5-HT2C receptor, behaviours that are not shown by the second compound. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved.