(-)-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 recently described by us. The (+)- and (-)-enantiomers 4 were prepared from the primary amine 8 by crystallisation of the (+)- and (-)-mandelic acid salts. The enantiomers reacted with propyl iodide and were demethylated 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 GTP-gamma S did not decrease the affinity of these compounds for 5-HT1A receptors, suggesting a partial agonist or antagonist profile. Adenylyl cyclase assays with rat hippocampal membranes showed that (-)-4 was totally inactive as an agonist over a wide concentration range in contrast to (+)-4 which was a partial agonist. (-)-4 (1 and 10 mu M) shifted the concentration-effect curve for the inhibition by 8-OH-DPAT of forskolin-stimulated cyclic AMP production to the right (pA(2) = 7.6), demonstrating a competitive interaction between the two drugs. (C) Elsevier, Paris.