Cholinergic effects of molecular segments of apomorphine and dopaminergic effects of N,N-dialkylated dopamines.
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.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000138:chemical synthesis / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000201:enzymology / Q000502:physiology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000502:physiology* / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010277:Parasympathomimetics / Q000633:toxicity; D051381:Rats; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000502:physiology
D010277:Parasympathomimetics; D000262:Adenylyl Cyclases; D001058:Apomorphine; D004298:Dopamine