Original Article

Relevance of stereo and quantum chemistry of four tetrahydroproto-berberines to their effects on dopamine receptors

Authors: Jian-Cheng Xuan, Guang-Da Lin, Guo-Zhang Jin, Yan Chen

Abstract

l-Tetrahydropalmatine(l-THP), l-corydalamine (l-CDL), l-stepholidine (l-SPD) and d-THP are the homologues of tetrahydroprotoberberines (THPB). They have a common structure with different hydroxyl groups substituting for methoxy groups (Fig 1). It has been demonstrated tbat the l-THPB had the characteristics of dopamine receptor antagonist in brain with sedative tranquillizing effect. The order of their potencies was l-SPD>l-CDL>l-THP. However, the enantiomor d-THP had no affinity to DA receptors. The molecular structures of 4 THPB were determined by X-ray diffraction method. The crystallographic parameters of t-SPD, l-CDL, l-THP and d-THP are respectively as follows: a = 1.0036, 1.0470,0.7436 and 0.7436 nm b=1.0772, 1.1608,1.1788 and l.170lnm c=1.5146, 0.7504,2.2282 and 2.2315 nm Their structures were solved by direct method and by a difference Fourier systhesis, then refined to R (isotropic factor) =0.1 (0.09-0.108) for 2012-2640 unique observable reflexions by least squares. The absolute configurations of 4 THPB crystal molecules were determined by Biloet pairs observation for 20 pairs of greatest anomalous contributions with the residuals (final factors) less than 0.04 (Tab 3). It has been found that the N atom in l-THPB molecules is oriented downward vs the horizontal plane of A ring, while He at the chiral carbon (C0) is oriented upward vs the plane. Such a common stereo-structure is considered to be a requirement of stereospecificity for l-THPB to dopamine receptors. However, just opposite to l-THP. the absolute configuration of d-THP is N-atom upward vs the plane of A ring and Ha downward. Thus it leads a steric hindrance to DA receptor binding. The distance between N atom and Ob,c,d at A ring or to D ring is 0.58-0.64 nm. which may be an optimum distance for DA receptor binding. Also the structural parameters have been demonstrated that the smaller the A-D dihedral angle. the easier the binding to the DA receptors. CND0/2 calculation of frontier orbital has showed that HOMO is in D ring. but not in A ring; while LUMO only in A ring and not in D ring. It is suggested that the conjugate ring A or/and D may form a 7r-7r interaction with an aromatic group (or groups) of DA receptor residues. The results of quantum calculation showed that l-SPD with two hydroxyl substitution for 2 methoxy groups possesses the most electronic densities around Ob and Oe and the highest binding energy levels for reaction correspond with the strongest affinity among l-THPB to DA receptor binding. It is presumed that the hydroxyl group would form hydrogen bond with the residue of DA receptors. Based on the above-mentioned results, a topography for l-THPB (Fig 3). especially in l-SPD. to DA receptors is proposed.
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