5-OXYGENATED N-ALKYL-2-AMINO-1-METHYLTETRALINS AND N,N-DIALKYL-2-AMINO-1-METHYLTETRALINS - EFFECTS OF STRUCTURE AND STEREOCHEMISTRY ON DOPAMINE-D2-RECEPTOR AFFINITY

The ability of a series of stereochemically well-defined 5-oxygenated 2-aminotetralins, consisting of dopamine-receptor agonists and antagonists, to displace [H-3]spiperone and [H-3]N-propylnorapomorphine (NPA) from calf-caudate dopamine receptor sites has been evaluated in-vitro. In addition, the partition coefficients of the compounds were determined to measure their lipophilicity. The data were compared with previously obtained in-vivo biochemical data (dopa accumulation in reserpine pretreated or non-pretreated rats). Compounds with 2S-configuration and a C5-hydroxy substituent have the highest affinity for NPA-binding sites and such derivatives also have the highest potency in-vivo. The 2R-derivatives are less efficacious and their affinity for NPA- and spiperone binding sites is influenced by their lipophilicity. On the basis of these results, a model is proposed in which the antagonists form two, and the agonists form three, strong intermolecular bonds with the D2-receptor. According to this model, the agonists, but not the antagonists, are able to donate a hydrogen bond from the phenolic hydroxyl to the receptor

CIRCULAR-DICHROISM SPECTROSCOPY OF 2-AMINOTETRALINS

The circular dichroism (CD) spectra of a series of oxygenated 2-(dipropylamino)tetralin derivatives are reported. On the basis of known absolute configurations and conformational preferences of the compounds, the validity of published correlations between the sign of the (1)L(b) Cotton effect and the three-dimensional structure was examined. Contrary to predictions, substitution in position 6 or 7 of the tetralin moiety did not change the sign of the (1)L(b) Cotton effect. An unexpected sign inversion was, however, observed in some of the compounds containing methyl substituents in the nonaromatic ring. The occurrence of this inversion was not correlated with a change in conformational behaviour and varied depending on the position and nature of the aromatic substituent. No correlations were obvious between the sign of the (1)L(b) Cotton effect and the absolute configuration and conformational preferences of the compounds. Therefore, at present, CD spectroscopy does not appear to be useful in assignments of the absolute configurations of 2-(dipropylamino)tetralin derivatives. (C) 1995 Wiley-Liss, Inc

DOPAMINERGIC 2-AMINOTETRALINS - AFFINITIES FOR DOPAMINE D-2-RECEPTORS, MOLECULAR-STRUCTURES, AND CONFORMATIONAL PREFERENCES

A combination of X-ray crystallography, NMR spectroscopy, and molecular mechanics (MMP2) calculations was used to determine the three-dimensional structures and conformational preferences of the enantiomers of 5-hydroxy-2-(di-n-propylamino)tetralin and their C1-methylated derivatives. In addition, the affinities of the compounds for striatal 3H-spiroperidol- and 3H-N-n-propylnorapomorphine-binding sites were determined. In the present series, the dopamine D2-receptor agonists have the S-configuration at the nitrogen-bearing carbon (C2), whereas the only established D2-receptor antagonist, 1S,2R-5-hydroxyl-1-methyl-2-(di-n-propylamino)tetralin (1S,2R-UH-242), has the opposite absolute configuration at C2. Two conformational parameters, the tetralin inversion angle (phi) and the dihedral angle tau(C1, C2, N, N-H or electron pair) (tau N), are shown to be critical for D2-receptor agonism; phi values around 0 degrees and tau N values around 60 degrees appear to be optimal. The low D2-affinity of 1S,2S-5-hydroxyl-1-methyl-2-(di-n-propylamino)tetralin seems to be related to its inability to assume a low-energy "D2-receptor agonistic conformation." It is noted that the common structural denominator between the D2-receptor antagonists 1S,2R-UH-242 and 6aS-apomorphine is their inability to assume "dopamine D2-receptor agonistic nitrogen electron pair orientation