Resolution of 5,6-Dihydroxy-2-(N,N-di-n-propylamino)tetralin in Relation to the Structural and Stereochemical Requirements for Centrally Acting Dopamine Agonists

Article abstract of DOI:10.1021/jm50001a024

The enantiomers of 5,6-dimethoxy-2-(N,N-dipropylamino)tetralin were prepared with use of (+)- and (-)-dibenzoyltartaric acid as the resolving agent.Ether cleavage with BBr3 gave the enantiomers of the dihydroxy compound 5,6-dihydroxy-2-(N,N-dipropylamino)tetralin (5,6-(OH)2-DPATN).The in vitro activities of (+)- and (-)-5,6-(OH)2-DPATN were evaluated in binding studies with rat striatal tissue with use of <3H>-N-n-propylnorapomorphine (NPA) as the ligand.IC₅₀ (nM) values for (-)- and (+)-5,6-(OH)2-DPATN were 2.5 and 400, respectively.The in vivo efficacy of the enantiomers was evaluated by examining their effects on the metabolism of dopamine in rat striatum.After a 0.5 μmol/kg ip injection of the (-) enantiomer, the concentrations of the metabolites HVA and DOPAC were reduced to 50percent of control values, whereas at this dose the (+) isomer was inactive.On the basis of these findings together with the stereochemical data of previously described DA agonists, a dopamine-receptor model has been developed which consists of two binding sites for the amine nitrogen of DA agonists in addition to a major binding site for the m-hydroxy group.The relevance of this model with its accessory features is discussed in relation to the structure and pharmacological data of different DA agonists.