3-AMINO-3,4-DIHYDRO-2H-1-BENZOPYRAN DERIVATIVES AS 5-HT1A RECEPTOR LIGANDS AND POTENTIAL ANXIOLYTIC AGENTS .2. SYNTHESIS AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF SPIRO[PYRROLIDINE-2,3'(2'H)-BENZOPYRAN] AND SPIRO[PIPERIDINE-2,3'(2'H)-BENZOPYRAN]

In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran der ivatives with high affinity for 5-HT1A receptors, we have prepared rig id spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationshi p approach mainly based on similarity indices. A series of spiro[pyrro lidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutio ns on the aromatic ring as well as on the extracyclic spiranic nitroge n atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and th e experimental binding values was observed with an average difference of 0.2 unit on log(ICE(50)). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a, 23) with a hig h selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D- 1, D-2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopy ran series, the dextrorotatory enantiomer (+)-11a showed better affini ty and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psycho tropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.