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

Abstract

− (±)-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 (pA 2 = 7.6), demonstrating a competitive interaction between the two drugs.