Design of agents for stimulation of neostriatal dopaminergic mechanisms

Abstract

Abstract The structure-activity requirements for stimulation of striatal dopaminergic mechanisms were investigated using a series of phenethylamine derivatives, apomorphine and isoapomorphine, and the intracerebral injection technique for direct application into the striatum. Asymmetric body posturing (unilateral injections in saline-and haloperidol-pretreated rats) and hyperactive/stereotyped be-behaviour (bilateral injections in nialamide-pretreated rats) were used as indices of dopaminergic stimulation. Of 24 phenethylamine derivatives studied, 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) possessed maximum activity. Alteration in length of the ethylamine side-chain, substitution of the α-C atom (α-methyldopamine) or hydroxylation of ß-C atom (noradrenaline) markedly reduced or abolished activity. Activity was also decreased by N-methyl substitution but epinine was active. The catechol moiety appeared essential for dopaminergic stimulation since the 3- or 4-hydroxyphenethylamines (tyramine, m-tyramine) were inactive and 2-(3,4-methylenedioxyphenyl)ethylamine was only weakly active. The marked dopamine-like activity of the 2-(3,4-diacetoxyphenyl)ethylamine compounds was attributed to their non-enzymic hydrolysis to dopamine in situ. The stereoselectivity of the dopamine-induced effects was assessed using trans and cis-2-(3,4-methylenedioxyphenyl)cyclopropylamine. The trans conformer was active and the importance of this conformation was further indicated by the inactivity of isoapomorphine compared with apomorphine. It is suggested that the results provide a rational basis for the design of drugs required to stimulate striatal dopamine receptors and that the intrastriatal injection technique may be useful in the detection of potential antiparkinson agents.