Structure--activity relationships of n-substituted dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene analogues: 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) analogues were synthesized and tested intraperitoneally 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 homologues. Of these, analogues with one alkyl group larger than propyl became inactive or their dopaminomimetic effect was reduced when the propyl was replaced with a larger group. N-Monosubstituted analogues were inactive as dopamine agonists. N-n-P-r-N-n-Bu-6,7-ADTN was six times more potent than N-n-propyl-N-n-pentyl- and N-n-propyl-N-phenethyldopamine but ten times less potent than apomorphine. The availability of an array of structurally related dopamine analogues with dopaminomimetic properties may make it possible to test the hypothesis that there are more than one type of dopamine receptor and that stereotypy and locomotor activity may have different central nervous system loci. Moreover, they may be of potential use in the treatment of parkinsonism and other extrapyramidal disorders.