STRUCTURE-ACTIVITY-RELATIONSHIPS OF N-SUBSTITUTED DOPAMINE AND 2-AMINO-6,7-DIHYDROXY-1,2,3,4-TETRAHYDRONAPHTHALENE ANALOGS - BEHAVIORAL-EFFECTS IN LESIONED AND RESERPINIZED MICE

N,N-Disubstituted dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) analogs were synthesized and tested i.p. in mice for dopamine agonism. Compounds inducing asymmetric postures in unilaterally caudectomized mice were further tested in mice treated with reserpine and .alpha.-methyl-p-tyrosine methyl ester. ED50 values determined for reversal of reserpine-induced catalepsy were used to rank drug potency and correlated with molecular structure. N-n-Propyl N-substituted compounds were more effective than other N,N-dialkyl homologs. Of these, analogs with 1 alkyl group larger than propyl became inactive or their dopaminomimetic effect was reduced when the propyl was replaced with a larger group. N-Monosubstituted analogs were inactive as dopamine agonists. N-n-Pr-N-n-Bu-6,7-ADTN was 6 times more potent than N-n-propyl-N-n-pentyl- and N-n-propyl-N-phenethyldopamine but 10 times less potent than apomorphine. The availability of an array of structurally related dopamine analogs with dopaminomimetic properties may make it possible to test the hypothesis that there are more than 1 type of dopamine receptor and that stereotypy and locomotor activity may have different CNS loci, and they may be of potential use in the treatment of parkinsonism and other extrapyramidal disorders.