(-)-5-METHYL-8-HYDROXY-(DI-N-PROPYLAMINO)TETRALIN - A NEW 5-HT1A RECEPTOR ANTAGONIST

(+/-)-5-Me-8-OH-DPAT 4 was synthesized by a new synthetic pathway rece ntly described by us. The (+)- and (-)-enantiomers 4 were prepared fro m the primary amine 8 by crystallisation of the (+)- and (-)-mandelic acid salts. The enantiomers reacted with propyl iodide and were demeth ylated by 48% HBr to the (+)- and (-)-4 compounds. These compounds had good affinity for 5-HT1A receptors (K-i = 32.9 +/- 0.8 and 45.6 +/- 2 nM, respectively) but lacked enantioselectivity. In contrast to 8-OH- DPAT, but similar to WAY 100635 and (+)-WAY 100135, the addition of GT P-gamma S did not decrease the affinity of these compounds for 5-HT1A receptors, suggesting a partial agonist or antagonist profile. Adenyly l cyclase assays with rat hippocampal membranes showed that (-)-4 was totally inactive as an agonist over a wide concentration range in cont rast to (+)-4 which was a partial agonist. (-)-4 (1 and 10 mu M) shift ed the concentration-effect curve for the inhibition by 8-OH-DPAT of f orskolin-stimulated cyclic AMP production to the right (pA(2) = 7.6), demonstrating a competitive interaction between the two drugs. (C) Els evier, Paris.