Dopaminergic 2-aminotetralins: affinities for dopamine D2-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 orientations."
D001058:Apomorphine / Q000031:analogs & derivatives / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009281:Naphthalenes / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism* / Q000494:pharmacology; D014316:Tritium; D014961:X-Ray Diffraction
D009281:Naphthalenes; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; D014316:Tritium; C006561:2-aminotetralin; D013134:Spiperone; C009074:N-n-propylnorapomorphine; D001058:Apomorphine