N-Alkylated 2-aminotetralins: central dopamine-receptor stimulating activity

Abstract

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.

In vitro and in vivo evaluation of the binding of the dopamine D2 receptor agonist11C-(R,S)-5-hydroxy-2-(di-n-propylamino)tetralin in rodents and nonhuman primate

“…In order to study the HA-state of the dopamine D2 receptor, we radiolabeled the well-known D2 receptor agonist, 5-OH-DPAT (McDermed et al, 1976;Hacksell et al, 1979). Radiosynthesis of the positron-emitting analog 11 C-5-OH-DPAT was carried out by using 11 Cpropionyl chloride (Shi et al, 1999).…”

A homologous series of N-alkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins: Central dopamine receptor antagonists showing profiles ranging from classical antagonism to selectivity for autoreceptors

“…These actions are well known for most neuroleptics used. In addition, the di-methyl analogue antagonized the locomotor hyperactivity and stereotypies induced by the potent DA receptor agonist DiPr-5, 6-ADTN (McDerreed et al, 1975;Hacksell et al, 1979;. Furthermore, it displaced DiPr-5, 6-ADTN from striatal binding sites.…”

“…Interestingly, Hacksell et aL (1979) reported that the N, N-di-n-butyl analogue to 5-hydroxy-2-aminotetralin is a very low-potent DA receptor agonist compared to the N, N-di-n-propyl analogue.…”

(R)‐ and (S)‐5‐hydroxy‐2‐(dipropylamino)tetralin (5‐OH DPAT): Assessment of optical purities and dopaminergic activities

“…2 It has served as a lead compound in several structureactivity relationship studies (see, for example, refs. 2-7) and certain analogues have been claimed to be of potential therapeutic use.'…”