8-Hydroxy-2-(alkylamino)tetralins and related compounds as central 5-hydroxytryptamine receptor agonists

Abstract

A series of 2-(alkylamino)tetralins related to 8-hydroxy-2-(di-n-propylamino)tetralin (21) were prepared and tested as dopamine (DA) and 5-hydroxytryptamine (5-HT) receptor agonists. Several of the compounds were potent 5-HT agonists devoid of DA-mimetic effects. N-Ethyl or N-propyl substitution of 8-hydroxy-2-aminotetralin gave the most potent agonists. It was shown that the most potent compound, (+)-21, has the 2R configuration. 5,8-Di-methoxy-2-(di-n-propylamino)tetralin (31) was found to be a weak DA agonist devoid of 5-HT activity. The corresponding indan derivative, 4,7-dimethoxy-2-(di-n-propylamino)indan (39), has been reported to be active on both DA and 5-HT receptors. The 5-HT-stimulating properties of compounds 21 and 39 as compared to the incapability of compound 31 to activate the 5-HT receptor is tentatively explained by the assumed mode of binding of the compounds to the 5-HT receptor.

Structure Activity Relationship of Homochiral 7-Substituted 1-Aminoindans as 5-HT1A Receptor Ligands

“…At the 5-HT 1A receptor site the R-enantiomers regularly show the higher affinity. As expected from the results of the structure activity relationships of the 2-aminotetralins [28] , the optimum is obtained with the di-n-propylamino substitution. The pK I values for the donor-type (-OH, -OCH 3 , -OC 3 H 7 ) substituted tertiary compounds are higher than those for the acceptor-type (-CONH 2 , -CN, -CONHCH 2 C 6 H 11 ) substituted ones.…”

“…A possible explanation for this exception is the great three-dimensional extension of the acceptor substituent. Arvidsson et al [28] have already shown that the orientation at the receptor depends on the aromatic substitution pattern. The R-(-)-7-propoxy-1-(din-propylamino)indan hydrochloride (R-(-)-30) ( pK I = 7.07±0.19) has the highest affinity of all tested compounds, but is about 45 times less active than the reference compound 8-OH-DPAT (36) (pK I = 8.70) ( Table 7).…”

“…Among a variety of other tried acids only embonic acid yields a crystalline salt. The 7-hydroxy-l-(di-n-propylamino)indan (28) is not directly accessible via the primary amine 21, but can be synthesized Table 1. Physical data of 7-substituted 1-amionoindans.…”

“…One of the most potent known selective 5-HT 1A agonists is the 8-hydroxy-2-(di-n-propylamino)tetralin [27] and numerous investigations have been undertaken to explain the structure-activity relationship in the group of 8-hydroxy-2-(alkylamino)tetralins and related compounds [28] . The aim of this study was to prove whether ring contraction of 8-substituted-2-(alkylamino) tetralins to the 7-substituted-1-(alkylamino)indans would improve potency and selectivity of the lead and does not violate the pharmacophore model of Arvidsson et al [53] .…”

Differential effects of (R)-, (R, S)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin on hippocampal serotonin release and induction of hypothermia in awake rats

“…Introduction 8-Hydroxy-2-(di-n-propylamin)tetralin (8-OH-DPAT), the prototypical 5-HT 1A receptor agonist (Arvidsson et al, 1981(Arvidsson et al, , 1984, has been widely used as a radioactive ligand to study the distribution of 5-HT 1A receptors (Gozlan et al, 1983) and to induce various physiological and behavioural responses in the rat (Hjorth, 1985;Tricklebank et al, 1985). The R-and S-enantiomers of 8-OH-DPAT have similar binding affinities to the 5-HT 1A receptors in the rat hippocampus (Cornfield et al, 1991;Foreman et al, 1995) and to the cloned h5-HT 1A receptors (Lejeune et al, 1997).…”