C3-methylated 5-hydroxy-2-(dipropylamino)tetralins: conformational and steric parameters of importance for central...

C3-Methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) have been synthesized and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations (MMP2). The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (2R,3S)-5-Hydroxy-3-methyl-2-(di-n-propylamino)tetralin [(-)-8] was demonstrated to be a highly potent DA receptor agonist, while the other new compounds were of low potency or inactive. Results obtained confirmed the hypothesis that the tetralin inversion angle phi and the direction of the N-electron pair (N-H) tau N are conformational parameters of critical importance for DA D2 receptor activation in the 2-aminotetralin series. The high potency of (-)-8 allowed an extension of a previously defined "partial DA D2 receptor excluded volume".