(-)-5-Methyl-8-hydroxy-(di-n-propylamino)tetralin: A new 5-HT(1A) receptor antagonist

Article abstract of DOI:10.1016/S0223-5234(98)80044-5

(±)-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-HT(1A) 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-γS did not decrease the affinity of these compounds for 5-HT(1A) 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 μM) shifted the concentration-effect curve for the inhibition by 8-OH-DPAT of forskolin-stimulated cyclic AMP production to the right (pA₂ = 7.6), demonstrating a competitive interaction between the two drugs.