Ginos J Z, Cotzias G C, Tolosa E, Tang L C, LoMonte A
J Med Chem. 1975 Dec;18(12):1194-1200. doi: 10.1021/jm00246a005.
The hydrochlorides of molecular segments of apomorphine [2-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline, 2-(3'4'-dihydroxybenzyl)piperidine, and 1,2,3,4-tetrahydroisoquinoline with their respective N-methyl and N-n-propyl homologs] and N,N-dialkylated dopamine compounds were synthesized and studied for (1) LD50 in intact mice; (2) stereotypy in intact mice; (3) curving of the body in unilaterally caudectomized mice; (4) rotation in 6-hydroxydopamine-lesioned rats, and (5) activation of adenylate cyclase in homogenates of mouse caudate nuclei. Instead of dopaminergic effects 1-(3',4'-dihydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline showed cholinergic ones. These effects were blocked in atropine-pretreated animals. Of the N,N-dialkylated dopamine compounds synthesized, the N-n-propyl-N-n-butyldopamine ranked in all tests as the strongest dopamine-receptor agonist and N-methyl-N-n-propyldopamine as the weakest. In contrast, N,N-dimethyldopamine and 1-(3,4-dihydroxyphenylethyl)piperidine showed no dopaminergic effects. The effectiveness of the dopaminergic agonists depended on the length of the N-alkyl substituents suggesting interactions with hydrophobic regions of the receptor site.
