Synthesis and dopaminergic activity of some halogenated mono- and dihydroxylated 2-aminotetralins

Abstract

In a series of 7,8-dihydroxy-1-phenyltetrahydro-3-benzazepine dopamine receptor agonists introduction of a chloro or fluoro substituent into the 6-position increases dopaminergic potency. Also, in this series replacement of the 7-hydroxyl group with a halogen results in inversion of activity from dopamine receptor agonist to antagonist. The present study was aimed at exploring the possibility that the structure-activity observations in the 3-benzazepine series of dopaminergic agents might be extrapolated to another class of dopamine receptor agonists, the 2-aminotetralins. Thus, a series of chloro- and fluoro-substituted mono- and dihydroxylated 2-aminotetralins was prepared and evaluated for dopaminergic properties in D-1 and D-2 receptor-related tests. Introduction of a chloro substituent into the 8-position of the prototype of this series, i.e. 2-amino-6,7-dihydroxytetralin (ADTN), resulted in a compound with a high degree of selectivity for the D-1 subpopulation of dopamine receptors; it was equally or more potent than ADTN in the D-1 receptor-related tests with greatly decreased effectiveness in the tests involving D-2 receptors. A similar effect was observed with 8-fluoro-ADTN; however, the N-(4-hydroxyphenethyl)-N-propyl derivative 4g of the 8-chloro-substituted ADTN showed marked D-2 binding affinity. Conversely, introduction of a chloro substituent into the 5-position of ADTN markedly decreased D-1 receptor affinity and efficacy. This effect was not seen with the related 5-fluoro derivative, suggesting D-1 receptors are more sensitive to bulk in the 5-position of ADTN than are the D-2 receptors. Replacement of either the 6- or 7-hydroxyl groups of ADTN with a chloro or fluoro substituent, in contrast, did not parallel the response seen in the benzazepine series (i.e., the compounds uniformly demonstrated less receptor affinity and did not have dopamine receptor antagonist activity); however, the decrease in agonist potency was less marked in the case of 2-amino-6-fluoro-7-hydroxytetralins than in the chlorinated monohydroxyaminotetralins. Thus, a parallelism in structure-activity relationships in the benzazepine and aminotetralin series of dopamine receptor agonists was not observed. The differences may reflect altered modes of receptor binding in the two series.

Preparation and Pharmacological Characterization of trans-2-Amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes as D2-like Dopamine Receptor Agonists

“…The results showed that the compounds, unlike DA, are resistant to degradation by COMT and cross the blood−brain barrier following peripheral administration. − Many fluorinated monophenolic compounds were prepared and evaluated for their dopaminergic properties on D 1 -like and D 2 -like receptors; the presence of the highly electronegative fluorine atom on the aromatic nucleous increases liposolubility, and the strong electronegative influence of fluorine could alter the physicochemical properties of the phenolic group and the affinity for DA receptors. Among these, 2-amino-6-fluoro-7-hydroxytetralin ( 1 ) was slightly selective for D 2 -like receptors, while some N-substituted 2-[4(3)-fluoro-3(4)-hydroxyphenyl)]ethylamines ( 2a , b ) showed some degree of selectivity for D 2 -like receptors. , In contrast, Kozlik et al showed that some substituted tetrahydroisoquinolines are selective for D 1 -like over D 2 -like receptors (with K i of 0.18 and 450 nM, respectively, for the exemplified compound, 3 )…”

Nucleophilic Deoxyfluorination of Catechols

“…However, the preparation of such phenols is not always easy and/or often requires many steps. Other preparation methods of them include the multistep transformation of fluorinated benzene derivatives ,, and the stepwise transformation of an ortho -functional group of the phenols to a fluorine atom, such as Balz–Schiemann reaction . On the other hand, direct conversion of a hydroxyl group of catechol derivatives into a fluorine atom provides a quite different approach for producing the functionalized ortho -fluorophenols, which is particularly attractive and effective when the catechols are abundantly available; however, there are no reports on such transformation.…”

Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents

“…Chemistry Synthesis of the target designed compounds 1a-l and 2a-l was achieved through the pathway shown in Scheme 1. Methylation of the phenolic hydroxyl group of 2-chloro-5-methylphenol (4) using dimethyl sulfate gave 1-chloro-2-methoxy-4-methylbenzene (5) 22 .…”