In order to define the structural requirements of N-substituents of 2-aminotetralins as central dopamine receptor agonists, a series of N-alkyl- and N,N-dialkyl-substituted 2-amino-5-hydroxy- and 2-amino-5-methoxytetralins have been synthesized and evaluated. The compounds were tested biochemically and behaviorally for dopaminergic activity. From the biochemical data it is concluded that an n-propyl group on the nitrogen is optimal for activity. The corresponding N-ethyl-substituted compounds are slightly less active, while the absence of N-ethyl or N-propyl groups give almost inactive compounds. It could be demonstrated that this is due to steric and not to lipophilic factors. It is suggested that a possible requirement for a potent agonist is that one of it N substituents must fit into a receptor cavity which, because of its size, can maximally accommodate an n-propyl but also smaller groups like ethyl or methyl. The active compounds appeared to give a similar relative pre- and postsynaptic stimulation and had also similar activities for the limbic system and for striatum. None of the compounds listed seemed to have central noradrenaline- or serotonin-receptor stimulating activity.

Thirty compounds related to the selective dopamine-autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine have been synthesized and tested for central dopamine-autoreceptor stimulating activity. The 3-(3-hydroxyphenyl)piperidine moiety seems indispensable for high potency and selectivity. Introduction of an additional hydroxyl group into the 4 position of the aromatic ring gives a compound with dopaminergic activity but lacking selectivity for autoreceptors. 3-(3-Hydroxyphenyl)-N-n-propylpyrrolidine, 3-(3-hydroxy)-N-n-propylperhydroazepine, and 3-(3-hydroxyphenyl)quinuclidine were all inactive. The most potent compounds were the N-isopropyl-, N-n-butyl-, N-n-pentyl-, and N-phenethyl-substituted 3-(3-hydroxyphenyl)piperidine derivatives. None of the compounds investigated seemed to have central noradrenaline- or serotonin-receptor stimulating activity.

N,N-Dialkylated monophenolic derivatives of trans-2-phenylcyclopropylamine were synthesized and tested for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor stimulating activity by use of a biochemical test method in rats. A hydroxy substituent in the 2- or 3-position of the phenyl ring was required for 5-HT-receptor stimulation. N,N-Diethyl or N,N-di-n-propyl substitution gave the most potent 5-HT-receptor agonists. The 4-hydroxy and 3,4-dihydroxy derivatives of trans-2-phenyl-N,N-di-n-propylcyclopropylamine were inactive at central DA and 5-HT receptors. In contrast, the corresponding 3-hydroxy derivative 18 and some of its derivatives weakly affected both DA and NE synthesis. Two of the most potent 5-HT-receptor agonists, trans-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine (8) and the 3-hydroxy isomer 18 were resolved into the enantiomers. The 1R,2S enantiomers of 8 and 18 displayed 5-HT activity, while the 1S,2R enantiomers were inactive. Compound (1R,2S)-18, but not (1R,2S)-8, weakly affected rat brain DA and NE synthesis.

No abstract

C1-Methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1) were synthesized and tested for central 5-HT and dopamine receptor activity by use of a biochemical test method in rats. cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin (8) was found to be a 5-HT receptor agonist. The (+)-enantiomer of 8 had a potency equal to that of 1, whereas (-)-8 and the trans isomer (+/-)-9 were inactive.