DERIVATIVES OF 2-(DIPROPYLAMINO)TETRALIN - EFFECT OF THE C8-SUBSTITUENT ON THE INTERACTION WITH 5-HT1A RECEPTORS

A series of 2-(dipropylamino)tetralin derivatives in which the C8 subs tituent is varied has been prepared and evaluated pharmacologically to explore the importance of the C8 substituent in the interaction of 2- aminotetralin-based ligands with serotonin (5-HT1A) receptors. Enantio pure derivatives were prepared by facile palladium-catalyzed reactions of the triflates of the enantiomers of 8-hydroxy-2-(dipropylamino)tet ralin (8-OH-DPAT, 1). The affinity of the compounds for the 5-HT1A rec eptors was evaluated by competition experiments with [H-3]-8-OH-DPAT i n rat hippocampal and cortical tissue. In addition, the compounds were evaluated for central 5-HT and dopamine receptor stimulating activity in vivo by use of biochemical and behavioral assays in rats. With the exception of the carboxy-substituted derivative which is devoid of 5- HT1A receptor affinity, the compounds have moderate to high affinities (K-i values range from 0.7 to 130 nM) for 5-HT1A receptors. Surprisin gly, several of the derivatives do not produce any apparent effects in vivo although they have fairly high 5-HT1A receptor affinities. Howev er, the methoxycarbonyl- and acetyl-substituted derivatives are potent 5-HT1A receptor agonists in vitro and exhibit in vitro affinities in the same range as the enantiomers of 1.