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.
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 mumol/kg ip injection of the (-) enantiomer, the concentrations of the metabolites HVA and DOPAC were reduced to 50% 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 sit 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.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009281:Naphthalenes / Q000302:isolation & purification*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000302:isolation & purification* / Q000494:pharmacology
D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C015842:2-(N,N-dipropyl)amino-5,6-dihydroxytetralin; D004298:Dopamine